Quinolone compound

ABSTRACT

The present invention provides a compound represented by the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R 1  is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R 2  is alkyl, alkoxy, haloalkoxy, a halogen atom, cyano, etc.; and R 3  is 7-oxo-7,8-dihydro-1,8-naphthyridinyl, 3-pyridyl, etc., or a salt thereof. The compound of the present invention has excellent antimicrobial activity against  Clostridium difficile  and is useful for the prevention or treatment of intestinal infection such as  Clostridium difficile -associated diarrhea.

TECHNICAL FIELD

The present invention relates to quinolone compounds and pharmaceuticaluse thereof.

BACKGROUND ART

Clostridium difficile infection is associated with consumption ofantibiotics which disrupt the normal microbial flora of the gut,allowing Clostridium difficile to establish itself and produce disease.Currently, only vancomycin or metronidazole is recommended for treatmentand many patients suffer from relapse on infection (Expert Opin. Ther.Patents (2010) 20(10), pp. 1389-1399).

EP2177214 A1 describes use of ozenoxacin for Clostridium difficile.

Some quinolone compounds useful as antibacterial agents are disclosed inJP1-319463 A, WO99/51588, WO99/03465, JP3-66301 B and WO99/07682.

SUMMARY OF INVENTION

The object of the present invention is to provide a novel quinolonecompound which has excellent antimicrobial activity, particularlyexcellent antimicrobial activity against Clostridium difficile. Anotherobject of the present invention is to provide a pharmaceuticalcomposition containing said quinolone compound, which is useful for theprevention or treatment of various infectious diseases includingantibiotics-associated diarrhea (AAD) such as Clostridiumdifficile-associated diarrhea (CDAD). A further object of the presentinvention is to provide a method for preventing or treating a bacterialinfection including AAD such as CDAD, which comprises administering saidquinolone compound to a human or an animal.

The present invention provides a quinolone compound, a pharmaceuticalcomposition comprising said compound, use of said compound, and a methodfor preventing or treating a bacterial infection, as described in items1 to 27 below.

Item 1. A compound represented by the formula (I)

whereinX is a hydrogen atom or a fluorine atom;R is a hydrogen atom or alkyl;R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or(2) phenyl optionally substituted by 1 to 3 halogen atoms;R² is a hydrogen atom; alkyl optionally substituted by 1 or 2substituents selected from the group consisting of a halogen atom andhydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro;amino; formyl; alkenyl or alkynyl; orR¹ and R² are bonded to form a 5- or 6-membered ring optionallysubstituted by alkyl;

R³ is

-   (1) a fused heterocyclic group of the formula

wherein

represents a single bond or a double bond,

X¹ is C(R⁵) or N,

R⁴ is a hydrogen atom or alkyl, and

R⁵ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) hydroxy,    -   (f) alkyl optionally substituted by 1 to 3 halogen atoms,    -   (g) alkenyl or alkynyl,    -   (h) aryl, or    -   (i) alkoxy optionally substituted by 1 to 3 halogen atoms,        when X¹ is C(R⁵), R⁴ and R⁵ are optionally bonded to form a 5-        or 6-membered ring optionally substituted by oxo,        said fused heterocyclic group is optionally substituted by 1 or        2 substituents selected from the group consisting of a halogen        atom, cyano, nitro, hydroxy and alkyl,

-   (2) a group of the formula

wherein

X² is C(R⁸) or N, and

R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkoxy and amino,    -   (g) alkenyl,    -   (h) alkynyl,    -   (i) aryl,    -   (j) formyl or CH═N—OH,    -   (k) carboxy,    -   (l) carbamoyl,    -   (m) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl, or    -   (n) alkenyloxy,

-   (3) a group of the formula

wherein

X³ and X⁴ are N, or

X³ is N and X⁴ is CR″, wherein R″ is hydrogen atom, amino, hydroxy,alkyl optionally substituted by 1 to 3 substituents selected from thegroup consisting of alkoxy and dimethylamino or mercapto, or

X³ is CH and X⁴ is N,

R′ is a hydrogen atom or alkyl optionally substituted by 1 to 3substituents selected from the group consisting of substituted hydroxyland amino, andR⁶ is as defined above,

-   (4) a group of the formula

wherein

represents a single bond or a double bond and R⁶ is as defined above,

-   (5) 3-pyridyl optionally substituted by 1 or 2 substituents selected    from the group consisting of    -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) amino,    -   (f) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkylamino,        dialkylamino and hydroxy,    -   (g) alkenyl, alkynyl    -   (h) aryl,    -   (i) cycloalkyl,    -   (j) alkoxy,    -   (k) alkylamino,    -   (l) dialkylamino,    -   (m) phenylamino optionally substituted by 1 to 3 halogen atoms,    -   (n) a cyclic amino group optionally substituted by        alkoxycarbonyl,    -   (o) formyl,    -   (p) carbamoyl optionally substituted by alkyl optionally        substituted by hydroxy, and    -   (q) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl,-   (6) 4-pyridyl optionally substituted by a halogen atom,-   (7) 5-pyrimidinyl optionally substituted by 1 or 2 substituents    selected from the group consisting of amino, alkylamino,    dialkylamino and carboxy,-   (8) 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, benzofuranyl,    benzothiophenyl, benzoxazolyl or benzothiazolyl, each optionally    substituted by 1 or 2 substituents selected from the group    consisting of    -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of amino, alkoxycarbonylamino,        alkylamino and dialkylamino,    -   (f) alkoxy,    -   (g) formyl,    -   (h) carboxy, and    -   (j) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkoxycarbonyl,        -   (ii) alkylcarbonyl optionally substituted by a substituent            selected from the group consisting of            -   (A) cycloalkyloxy optionally substituted by 1 to 3                alkyl,            -   (B) alkylamino,            -   (C) dialkylamino,            -   (D) a cyclic amino group optionally substituted by                alkoxycarbonyl, and            -   (E) a halogen atom,        -   (iii) phenylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of alkyl and            alkoxy,        -   (iv) cycloalkylcarbonyl,        -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group            optionally substituted by alkyl optionally substituted by 1            to 3 halogen atoms,        -   (vi) benzylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of a halogen            atom and alkoxy,        -   (vii) arylsulfonyl optionally substituted by alkoxy,        -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1            to 3 substituents selected from the group consisting of            alkyl and oxo,        -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group            optionally substituted by 1 to 3 alkyl, and        -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl,-   (9) a group of the formula

whereinone of Y¹, Y², Y³ and Y⁴ is N or N⁺(—O⁻), and the remaining three areeach C(R²⁵), C(R²⁶) and C(R²⁷),

W is O, S, NH or N(R²³)

R²³ is a hydrogen atom or alkyl, andR²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,    -   (b) cyano, or    -   (c) nitro,

-   (10) a group of the formula

whereinR²⁸ is a hydrogen atom or hydroxy, andR²⁹ is a hydrogen atom or alkyl,

-   (11) a group of the formula

wherein

X⁵ is C(R¹¹) or N, X⁶ is CH₂, C(═O), O, S, SO₂ or N(R¹²), X⁷ is CH(R¹³),C(═O) or N(R¹⁴), X⁸ is CH(R¹⁵) or C(═O),

R¹⁰, R¹² and R¹⁴ are each independently,

-   -   (a) a hydrogen atom or    -   (b) alkyl, and        R¹¹, R¹³ and R¹⁵ are each independently,    -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) alkylamino,    -   (g) dialkylamino,    -   (h) alkyl optionally substituted by hydroxy, or    -   (i) alkenyl,        when X⁵ is C(R¹¹), R¹⁰ and R¹¹ are optionally bonded to form a        5- or 6-membered ring optionally substituted by alkyl or oxo,        and when X⁶ is N(R¹²) and X⁷ is CH(R¹³), R¹² and R¹³ are        optionally bonded to form a 5- or 6-membered ring,

-   (12) a group of the formula

wherein R¹⁶ is

-   -   (a) a hydrogen atom,    -   (b) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of cyano, alkylamino and dialkylamino,    -   (c) alkenyl optionally substituted by carboxy,    -   (d) formyl,    -   (e) carboxy,    -   (f) carbamoyl,    -   (g) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or        hydroxy,    -   (h) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or    -   (i) cyano,

-   (13) a group of the formula

whereinR¹⁸ is a hydrogen atom or alkyl optionally substituted by 1 to 3substituents selected from the group consisting of a halogen atom andphenyl,n is 0 or 1,R¹⁹, R²⁰ and R³³ are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of        -   (i) a halogen atom,        -   (ii) cyano,        -   (iii) hydroxy,        -   (iv) amino,        -   (v) alkylamino,        -   (vi) dialkylamino, and        -   (vii) a cyclic amino group optionally substituted by alkyl,    -   (e) alkoxy,    -   (f) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkylcarbonyl optionally substituted by a cyclic amino            group,        -   (ii) alkylsulfonyl,        -   (iii) carbamoyl,        -   (iv) alkyl, cycloalkyl or cycloalkylalkyl, and        -   (v) 5- to 10-membered saturated heterocyclic group,    -   (g) carboxy,    -   (h) alkoxycarbonyl,    -   (i) carbamoyl optionally substituted by alkyl optionally        substituted by amino, alkylamino, dialkylamino or        alkoxycarbonylamino,    -   (j) formyl,    -   (k) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl,    -   (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl        optionally substituted by alkylamino or dialkylamino,    -   (m) nitro,    -   (n) a 5- to 10-membered saturated heterocyclic group optionally        substituted by amino,    -   (o) phenyl, or    -   (p) —NHC(SMe)═CHCN,

-   (14) a group of the formula

wherein

R³⁰ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom and hydroxy,    -   (e) alkenyl,    -   (f) alkynyl,    -   (g) alkoxy,    -   (h) formyl,    -   (i) —CH═N—OH, or    -   (j) carbamoyl,

-   (15) naphthyl or isochromenyl,

-   (16) quinolyl or isoquinolyl, or their oxide derivatives,

-   (17) a group of the formula

-   (18) a group of the formula

wherein

U is O or S, and R³¹ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) alkyl optionally substituted by 1 to 3 halogen atoms,    -   (d) carboxy,    -   (e) nitro,    -   (f) cyano, or    -   (g) amino,

-   (19) a group of the formula

wherein

R³² is

-   -   (a) a halogen atom,    -   (b) phenyl, or    -   (c) a group of the formula

-   (20) a group of the formula

whereinR³⁴ and R³⁵ are each independently,

-   -   (a) a hydrogen atom, or    -   (b) aminoalkyl,        or        R³⁴ and R³⁵ are bonded to form a 6-membered ring optionally        substituted by amino or oxo,

-   (21) a group of the formula

wherein R³⁶ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) nitro, or    -   (d) thienyl, or

-   (22) a group of the formula

or a salt thereof.

Item 1A. The compound of item 1, wherein

X is a hydrogen atom or a fluorine atom;R is a hydrogen atom or alkyl;R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or(2) phenyl optionally substituted by 1 to 3 halogen atoms;R² is alkyl, alkoxy, haloalkoxy, a chlorine atom or cyano; orR¹ and R² are bonded to form a 5- or 6-membered ring optionallysubstituted by alkyl; and

R³ is

-   (1) a fused heterocyclic group of the formula

wherein

represents a single bond or a double bond,

X¹ is C(R⁵) or N,

R⁴ is a hydrogen atom or alkyl, and

R⁵ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) hydroxy,    -   (f) alkyl optionally substituted by 1 to 3 halogen atoms,    -   (g) alkenyl or alkynyl,    -   (h) aryl, or    -   (i) alkoxy optionally substituted by 1 to 3 halogen atoms,        when X¹ is C(R⁵), R⁴ and R⁵ are optionally bonded to form a 5-        or 6-membered ring optionally substituted by oxo,        said fused heterocyclic group is optionally substituted by 1 or        2 substituents selected from the group consisting of a halogen        atom, cyano, nitro, hydroxy and alkyl,

-   (2) a group of the formula

wherein

X² is C(R⁶) or N, and

R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkoxy and amino,    -   (g) alkenyl,    -   (h) alkynyl,    -   (i) aryl,    -   (j) formyl or CH═N—OH,    -   (k) carboxy,    -   (l) carbamoyl, or    -   (m) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl,

-   (3) a group of the formula

wherein

X³ and X⁴ are N, or

X³ is N and X⁴ is CR″, wherein R″ is a hydrogen atom, amino, hydroxy,alkyl or mercapto, or

X³ is CH and X⁴ is N,

R′ is a hydrogen atom or alkyl optionally substituted by 1 to 3substituents selected from the group consisting of substituted hydroxyand amino, andR⁶ is as defined above,

-   (4) a group of the formula

wherein

represents a single bond or a double bond and R⁶ is as defined above,

-   (5) 3-pyridyl optionally substituted by 1 or 2 substituents selected    from the group consisting of    -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) amino,    -   (f) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkylamino,        dialkylamino and hydroxy,    -   (g) alkenyl or alkynyl,    -   (h) aryl,    -   (i) cycloalkyl,    -   (j) alkoxy,    -   (k) alkylamino,    -   (l) dialkylamino,    -   (m) phenylamino optionally substituted by 1 to 3 halogen atoms,    -   (n) a cyclic amino group optionally substituted by        alkoxycarbonyl,    -   (o) formyl,    -   (p) carbamoyl optionally substituted by alkyl optionally        substituted by hydroxy, and    -   (q) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl,-   (6) 4-pyridyl optionally substituted by a halogen atom,-   (7) 5-pyrimidinyl optionally substituted by 1 or 2 substituents    selected from the group consisting of amino, alkylamino,    dialkylamino and carboxy,-   (8) 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, benzofuranyl,    benzothiophenyl, benzoxazolyl or benzothiazolyl, each optionally    substituted by 1 or 2 substituents selected from the group    consisting of    -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of amino, alkoxycarbonylamino,        alkylamino and dialkylamino,    -   (f) alkoxy,    -   (g) formyl,    -   (h) carboxy, and    -   (j) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkoxycarbonyl,        -   (ii) alkylcarbonyl optionally substituted by a substituent            selected from the group consisting of            -   (A) cycloalkyloxy optionally substituted by 1 to 3                alkyl,            -   (B) alkylamino,            -   (C) dialkylamino,            -   (D) a cyclic amino group optionally substituted by                alkoxycarbonyl, and            -   (E) a halogen atom,        -   (iii) phenylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of alkyl and            alkoxy,        -   (iv) cycloalkylcarbonyl,        -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group            optionally substituted by alkyl optionally substituted by 1            to 3 halogen atoms,        -   (vi) benzylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of a halogen            atom and alkoxy,        -   (vii) arylsulfonyl optionally substituted by alkoxy,        -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1            to 3 substituents selected from the group consisting of            alkyl and oxo,        -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group            optionally substituted by 1 to 3 alkyl, and        -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl,-   (9) a group of the formula

whereinone of Y¹, Y², Y³ and Y⁴ is N or N⁺(—O⁻), and the remaining three areeach C(R²⁵), C(R²⁶) and C(R²⁷),

W is O, S or N(R²³)

R²³ is a hydrogen atom or alkyl, andR²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,    -   (b) cyano, or    -   (c) nitro,

-   (10) a group of the formula

whereinR²⁸ is a hydrogen atom or hydroxy, andR²⁹ is a hydrogen atom or alkyl,

-   (11) a group of the formula

wherein

X⁵ is C(R¹¹) or N, X⁶ is CH₂, C(═O), O, S, SO₂ or N(R¹²), X⁷ is CH(R¹³),C(═O) or N(R¹⁴), X⁸ is CH(R¹⁵) or C(═O),

R¹⁰, R¹² and R¹⁴ are each independently,

-   -   (a) a hydrogen atom or    -   (b) alkyl, and        R¹¹, R¹³ and R¹⁵ are each independently,    -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) alkylamino,    -   (g) dialkylamino,    -   (h) alkyl optionally substituted by hydroxy, or    -   (i) alkenyl,        when X⁵ is C(R¹¹), R¹⁰ and R¹¹ are optionally bonded to form a        5- or 6-membered ring optionally substituted by alkyl or oxo,        and when X⁶ is N(R¹²) and X⁷ is CH(R¹³), R¹² and R¹³ are        optionally bonded to form a 5- or 6-membered ring,

-   (12) a group of the formula

wherein R¹⁶ is

-   -   (a) a hydrogen atom,    -   (b) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of cyano, alkylamino and dialkylamino,    -   (c) alkenyl optionally substituted by carboxy,    -   (d) formyl,    -   (e) carboxy,    -   (f) carbamoyl,    -   (g) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or        hydroxy,    -   (h) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or    -   (i) cyano,

-   (13) a group of the formula

whereinR¹⁸ is a hydrogen atom or alkyl optionally substituted by 1 to 3substituents selected from the group consisting of a halogen atom andphenyl, andR¹⁹ and R²⁰ are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) alkyl Optionally substituted by 1 to 3 substituents selected        from the group consisting of        -   (i) a halogen atom,        -   (ii) cyano,        -   (iii) hydroxy,        -   (iv) amino,        -   (v) alkylamino,        -   (vi) dialkylamino, and        -   (vii) a cyclic amino group optionally substituted by alkyl,    -   (e) alkoxy,    -   (f) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkylcarbonyl optionally substituted by a cyclic amino            group,        -   (ii) alkylsulfonyl,        -   (iii) carbamoyl, and        -   (iv) alkyl or cycloalkyl,    -   (g) carboxy,    -   (h) alkoxycarbonyl,    -   (i) carbamoyl optionally substituted by alkyl optionally        substituted by amino, alkylamino, dialkylamino or        alkoxycarbonylamino,    -   (j) formyl,    -   (k) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl,    -   (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl        optionally substituted by alkylamino or dialkylamino, or    -   (m) nitro,

-   (14) a group of the formula

wherein

R³⁰ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom and hydroxy,    -   (e) alkenyl,    -   (f) alkynyl,    -   (g) alkoxy,    -   (h) formyl, or    -   (i) —CH═N—OH,

-   (15) naphthyl or isochromenyl, or

-   (16) quinolyl or isoquinolyl, or oxide derivative thereof,    or a salt thereof.

Item 2. The compound of item 1 or 1A, wherein X is a fluorine atom, or asalt thereof.

Item 3. The compound of item 1 or 1A, wherein R³ is a fused heterocyclicgroup of the formula

wherein

, X¹ and R⁴ are as defined in item 1, and said fused heterocyclic groupis optionally substituted by 1 or 2 substituents selected from the groupconsisting of a halogen atom, cyano, nitro, hydroxy and alkyl, or a saltthereof.

Item 4. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein X², R⁶ and R⁷ are as defined in item 1, or a salt thereof.

Item 5. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein X³, X⁴, R⁶ and R′ are as defined in item 1, or a salt thereof.

Item 6. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein

and R⁶ are as defined in item 1, or a salt thereof.

Item 7. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein R²² is

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkylamino,        dialkylamino and hydroxy,    -   (e) alkenyl or alkynyl,    -   (f) aryl,    -   (g) cycloalkyl,    -   (h) alkoxy,    -   (i) formyl, or    -   (j) carbamoyl optionally substituted by alkyl optionally        substituted by hydroxy,        or a salt thereof.

Item 8. The compound of item 1 or 1A, wherein R³ is 5-pyrimidinylsubstituted by 1 or 2 substituents selected from the group consisting ofamino, alkylamino, dialkylamino and carboxy, or a salt thereof.

Item 9. The compound of item 1 or 1A, wherein R³ is 2-indolyl optionallysubstituted by 1 or 2 substituents selected from the group consisting of

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of amino, alkoxycarbonylamino,        alkylamino and dialkylamino,    -   (f) alkoxy,    -   (g) formyl,    -   (h) carboxy, and    -   (j) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkoxycarbonyl,        -   (ii) alkylcarbonyl optionally substituted by a substituent            selected from the group consisting of            -   (A) cycloalkyloxy optionally substituted by 1 to 3                alkyl,            -   (B) alkylamino,            -   (C) dialkylamino,            -   (D) a cyclic amino group optionally substituted by                alkoxycarbonyl, and            -   (E) a halogen atom,        -   (iii) phenylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of alkyl and            alkoxy,        -   (iv) cycloalkylcarbonyl,        -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group            optionally substituted by alkyl optionally substituted by 1            to 3 halogen atoms,        -   (vi) benzylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of a halogen            atom and alkoxy,        -   (vii) arylsulfonyl optionally substituted by alkoxy,        -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1            to 3 substituents selected from the group consisting of            alkyl and oxo,        -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group            optionally substituted by 1 to 3 alkyl, and        -   (x) —C(═N—CN)—SR⁹ wherein R⁵ is alkyl,            or a salt thereof.

Item 10. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein Y¹, Y², Y³, Y⁴, W and R²⁴ are as defined in item 1, or a saltthereof.

Item 11. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein R²⁸ and R²⁹ are as defined in item 1, or a salt thereof.

Item 12. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein X⁵, X⁶, X⁷, X⁸ and R¹⁰ are as defined in item 1, or a saltthereof.

Item 13. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein R^(16a) is

-   -   (a) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of cyano, alkylamino and dialkylamino,    -   (b) alkenyl optionally substituted by carboxy,    -   (c) formyl,    -   (d) carboxy,    -   (e) carbamoyl,    -   (f) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or        hydroxy,    -   (g) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or    -   (h) cyano,        or a salt thereof.

Item 14. The compound of item 1 or 1A, wherein R³ is a group of theformula

whereinR^(18a) is alkyl, and

R^(19a) is

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of        -   (i) a halogen atom,        -   (ii) cyano,        -   (iii) hydroxy,        -   (iv) amino,        -   (v) alkylamino,        -   (vi) dialkylamino, and        -   (vii) a cyclic amino group optionally substituted by alkyl,    -   (d) alkoxy,    -   (e) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkylcarbonyl optionally substituted by a cyclic amino            group,        -   (ii) alkylsulfonyl,        -   (iii) carbamoyl, and        -   (iv) alkyl or cycloalkyl,    -   (f) carboxy,    -   (g) alkoxycarbonyl,    -   (h) carbamoyl optionally substituted by alkyl optionally        substituted by amino, alkylamino, dialkylamino or        alkoxycarbonylamino,    -   (i) formyl,    -   (j) a 5- to 10-membered aromatic heterocyclic group optionally        substituted by alkyl,    -   (k) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl        optionally substituted by alkylamino or dialkylamino, or    -   (l) nitro,        or a salt thereof.

Item 15. The compound of item 1 or 1A, wherein R³ is a group of theformula

wherein R³⁰ is as defined in item 1, or a salt thereof.

Item 16. The compound of item 1 or 1A, wherein R³ is naphthyl orisochromenyl, or a salt thereof.

Item 17. The compound of item 1 or 1A, wherein R³ is quinolyl orisoquinolyl, or oxide derivative thereof, or a salt thereof.

Item 18. The compound of item 1 or 1A, wherein R is a hydrogen atom, ora salt thereof.

Item 19. The compound of item 1 or 1A, wherein R¹ is cyclopropyl,2-fluorocyclopropyl or 2,4-difluorophenyl, or a salt thereof.

Item 20. The compound of item 1 or 1A, wherein R² is methyl, methoxy ora chlorine atom, or a salt thereof.

Item 21. A pharmaceutical composition comprising a compound of item 1 or1A or a salt thereof and a pharmaceutically acceptable carrier.

Item 22. An antimicrobial agent comprising a compound of item 1 or 1A ora salt thereof.

Item 23. A compound of item 1 or 1A or a salt thereof for use as amedicament.

Item 24. A compound of item 1 or 1A or a salt thereof for use as anantimicrobial agent.

Item 25. A compound of item 1 or 1A or a salt thereof for use in theprevention or treatment of a bacterial infection.

Item 26. Use of a compound of item 1 or 1A or a salt thereof for themanufacture of a medicament for preventing or treating a bacterialinfection.

Item 27. A method for preventing or treating a bacterial infection whichcomprises administering an effective amount of a compound of item 1 or1A or a salt thereof to a human or an animal.

The compound of the formula (I) or a salt thereof (hereinafter sometimesto be abbreviated as compound (I)) has excellent antibacterial activityagainst various gram positive and gram negative bacteria, and is usefulfor the prevention or treatment of various infectious diseases inducedby various bacteria in human, other animals and fish and is also usefulas an external antimicrobial or disinfectant agent for medicalinstruments or the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the results of the animals administered withcompound 2-18 in Experimental Example 2.

FIG. 2 is a graph showing the results of the animals administered withvancomycin in Experimental Example 2.

DETAILED DESCRIPTION OF THE INVENTION

Specific examples of groups in the formula (I) are as follows.

Examples of “halogen atom” include fluorine atom, chlorine atom, bromineatom, and iodine atom.

Examples of “alkyl” and “alkyl” moiety in “alkylamino”, “dialkylamino”,“alkylcarbonyl”, “cycloalkylalkylsulfonyl”, “cycloalkylalkyl”,“aminoalkyl” and “alkylsulfonyl” include straight or branched C₁₋₆ alkylsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-ethylpropyl, isopentyl, neopentyl, tert-pentyl,hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl,3-methylpentyl, etc.

Examples of “alkenyl” include straight or branched C₂₋₆ alkenyl such asvinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,l-methyl-2-propenyl, 2-pentenyl, 2-hexenyl, etc.

Examples of “alkynyl” include straight or branched C₂₋₆ alkynyl such asethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl,2-pentynyl, 2-hexynyl, etc.

Examples of “alkoxy” and “alkoxy” moiety in “haloalkoxy”,“alkoxycarbonyl” and “alkoxycarbonylamino” include straight or branchedC₁₋₆ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, 3-methylpentyloxy,etc.

Examples of “haloalkoxy” include straight or branched C₁₋₆ alkoxysubstituted by 1 to 3 halogen atoms. Examples thereof includefluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy,dichlorofluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy,3,3,3-trifluoropropoxy, 2-chloropropoxy, 3-chloropropoxy,3-bromopropoxy, 4,4,4-trifluorobutoxy, 2-chlorobutoxy, 4-chlorobutoxy,4-bromobutoxy, 5,5,5-trifluoropentyloxy, 5-chloropentyloxy,6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc. Preferable examplesthereof include difluoromethoxy.

Examples of “alkenyloxy” include straight or branched C₂₋₆ alkenyloxysuch as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy,2-butenyloxy, 3-butenyloxy, 1-methyl-2-propenyloxy, 2-pentenyloxy,2-hexenyloxy, etc.

Examples of “aryl” and “aryl” moiety in “arylsulfonyl.” include C₆₋₁₄(preferably C₆₋₁₀) aryl such as phenyl, naphthyl (e.g., 1-naphthyl,2-naphthyl), etc. Preferable examples thereof include phenyl.

Examples of “5- to 10-membered aromatic heterocyclic group” and “5- to10-membered aromatic heterocyclyl” moiety in “5- to 10-membered aromaticheterocyclylcarbonyl group” and “5-to 10-membered aromaticheterocyclylsulfonyl group” include 5-to 10-membered (preferably 5- or6-membered) aromatic heterocyclic group containing 1 to 4 (preferably 1to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom,an oxygen atom and a sulfur atom. Examples thereof include furyl,thienyl, pyrrolyl, pyrazolyl, imidazoiyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, isoxazolyl, oxazolyl,furazanyl, isothiazolyl, thiazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl,isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl,isoindolyl, indolizinyl, indazolyl, benzimidazolyl, benzotriazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,purinyl, quinolyl, isoquinolyl, quinolizinyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, pteridinyl, etc. Preferableexamples thereof include pyrrolyl, imidazolyl, oxazolyl, triazolyl(e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, pyridyl (e.g.,2-pyridyl, 3-pyridyl, 4-pyridyl), benzimidazolyl, etc.

Examples of “alkylamino” include C₁₋₆ alkylamino such as methylamino,ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,sec-butylamino, tert-butylamino, pentylamino, isopentylamino,neopentylamino, tert-pentylamino, hexylamino, etc.

Examples of “dialkylamino” include di(C₁₋₆ alkyl)amino such asdimethylamino, diethylamino, dipropylamino, diisopropylamino,dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino,dipentylamino-, di(tert-pentyl)amino, dihexylamino, ethylmethylamino,etc.

Examples of “aminoalkyl” include amino-C₁₋₆ alkyl such as aminomethyl,2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl,etc.

Examples of “cycloalkyl” and “cycloalkyl” moiety in “cycloalkyloxy”,“cycloalkylcarbonyl”, “cycloalkylalkyl” and “cycloalkylalkylsulfonyl”include C₃₋₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, norbornanyl (e.g., 2-norbornanyl),etc.

Examples of “cycloalkylalkyl” include C₃₋₆ cycloalkyl-C₁₋₆ alkyl such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, norbornanylmethyl(e.g., norbornan-2-ylmethyl), etc.

Examples of “cyclic amino group” includes a 4- to 7-membered (preferably5- or 6-membered) cyclic amino group containing one nitrogen atom andoptionally further containing one heteroatom selected from a nitrogenatom, an oxygen atom and a sulfur atom. Examples thereof include1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl,piperidino, 1-piperazinyl, morpholino, thiomorpholino, 1-azepanyl,1,4-oxazepan-4-yl, etc. Preferable examples thereof include1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino,etc.

Examples of “alkoxycarbonyl” include C₁₋₆ alkoxy-carbonyl wherein thealkoxy moiety is C₁₋₆ alkoxy. Examples thereof include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, etc.

Examples of “alkoxycarbonylamino” include C₁₋₆ alkoxy-carbonylaminowherein the alkoxy moiety is C₁₋₆ alkoxy. Examples thereof includemethoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino,sec-butoxycarbonylamino, tert-butoxycarbonylamino,pentyloxycarbonylamino, hexyloxycarbonylamino, etc.

Examples of “alkylcarbonyl” include C₁₋₆ alkyl-carbonyl wherein thealkyl moiety is C₁₋₆ alkyl. Examples thereof include acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl,isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl,hexylcarbonyl, etc.

Examples of “cycloalkyloxy” include C₃₋₈ cycloalkyloxy such ascyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, cyclooctyloxy, etc.

Examples of “cycloalkylcarbonyl” include C₃₋₈ cycloalkylcarbonyl such ascyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, etc.

Examples of “5- to 10-membered aromatic heterocyclylcarbonyl group”include a 5- to 10-membered (preferably 5- or 6-membered) aromaticheterocyclylcarbonyl group wherein the heterocyclyl moiety contains 1 to4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected froma nitrogen atom, an oxygen atom and a sulfur atom. Examples of theheterocyclyl moiety are same as the examples of the 5- to 10-memberedaromatic heterocyclic group mentioned above. Preferable examples of “5-to 10-membered aromatic heterocyclylcarbonyl group” includepyridylcarbonyl (e.g., 2-pyridylcarbonyl, 3-pyridylcarbonyl,4-pyridylcarbonyl).

Examples of “arylsulfonyl” include C₆₋₁₄ (preferably C₆₋₁₀) arylsulfonylsuch as phenylsulfonyl, naphthylsulfonyl (e.g., 1-naphthylsulfonyl,2-naphthylsulfonyl), etc. Preferable examples thereof includephenylsulfonyl.

Examples of “cycloalkylalkylsulfonyl” include C₃₋₈ cycloalkyl-C₃₋₆alkylsulfonyl such as cyclopropylmethylsulfonyl,cyclobutylmethylsulfonyl, cyclopentylmethylsulfonyl,cyclohexylmethylsulfonyl, cycloheptylmethyl sulfonyl,cyclooctylmethylsulfonyl, norbornanylmethylsulfonyl (e.g.,norbornan-2-ylmethylmethylsulfonyl), etc.

Examples of “5- to 10-membered aromatic heterocyclylsulfonyl group”include a 5- to 10-membered (preferably 5- or 6-membered) aromaticheterocyclylsulfonyl group wherein the heterocyclyl moiety contains 1 to4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected froma nitrogen atom, an oxygen atom and a sulfur atom. Examples of theheterocyclyl moiety are same as the examples of the 5- to 10-memberedaromatic heterocyclic group mentioned above. Preferable examples of “5-to 10-membered aromatic heterocyclylsulfonyl group” includeimidazolylsulfonyl.

Examples of “alkylsulfonyl” include C₁₋₆ alkylsulfonyl wherein the alkylmoiety is C₁₋₆ alkyl. Examples thereof include methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,hexylsulfonyl, etc.

Examples of “cyclopropyl optionally substituted by 1 to 3 halogen atoms”include cyclopropyl optionally substituted by 1 fluorine atom such ascyclopropyl, 2-fluorocyclopropyl, etc.

Examples of “phenyl optionally substituted by 1 to 3 halogen atoms”include phenyl substituted by two fluorine atoms such as2,4-difluorophenyl, etc.

Examples of “5- to 10-membered saturated heterocyclic group” include a5- to 10-membered (preferably 5- or 6-membered) saturated heterocyclicgroup containing 1 to 4 (preferably 1 to 3, more preferably 1 or 2)heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfuratom. Examples thereof include pyrrolidinyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, etc.

Examples of “6-membered ring optionally substituted by amino or oxo”formed by R³⁴ and R³⁵ include a 6-membered ring optionally containingone nitrogen atom, and said ring is optionally substituted by amino oroxo. Examples thereof include cyclohexene and dihydropyridine, eachoptionally substituted by 5 amino or oxo.

Examples of “5- or 6-membered ring optionally substituted by alkyl”formed by R¹ and R² include a 5- or 6-membered (preferably 6-membered)ring containing one nitrogen atom and optionally further containing oneoxygen atom, and said ring is optionally substituted by alkyl.Preferably, R¹ and R² are optionally bonded to form —O—CH₂—CH (CH₃)—wherein the oxygen atom is bonded to the phenyl ring of the quinolonering as shown below.

Examples of “5- or 6-membered ring optionally substituted by oxo” formedby R⁴ and R⁵ include a 5- or 6-membered (preferably 6-membered) ringcontaining one nitrogen atom and optionally further containing oneoxygen atom, and said ring is optionally substituted by oxo. Preferably,R⁴ and R⁵ are optionally bonded to form —CH₂—O—(C═O)— wherein thecarbonyl is bonded to the phenyl ring of the quinolone ring as shownbelow.

Examples of “5- or 6-membered ring optionally substituted by alkyl oroxo” formed by R¹⁰ and R¹¹ include a 5- or 6-membered (preferably5-membered) ring containing 2 or 3 nitrogen atoms, and said ring isoptionally substituted by alkyl or oxo. Preferably, R¹⁰ and R¹¹ areoptionally bonded to form —(C═O)—NH—, —C(R³¹)═N— or —N═N— wherein R³¹ isa hydrogen atom or alkyl, and the nitrogen atom is bonded to the phenylring of the fused ring, as shown below.

Examples of “5- or 6-membered ring” formed by R¹² and R¹³ include a 5-or 6-membered (preferably 6-membered) ring containing one nitrogen atom.Preferably, R¹² and R¹³ are optionally bonded to form —(CH₂)₄— as shownbelow.

X is a hydrogen atom or a fluorine atom, preferably, a fluorine atom.

R is a hydrogen atom or alkyl, preferably, a hydrogen atom.

R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or(2) phenyl optionally substituted by 1 to 3 halogen atoms, preferably,cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl.

R² is a hydrogen atom; alkyl optionally substituted by 1 or 2substituents selected from the group consisting of a halogen atom andhydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro;amino; formyl; alkenyl or alkynyl, preferably, alkyl, alkoxy,haloalkoxy, a chlorine atom or cyano, more preferably, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkoxy substituted by 1 to 3 halogen atoms, a chlorine atomor cyano, still more preferably, methyl, methoxy or a chlorine atom.

Examples of a fused heterocyclic group of the formula (A) or (B) includea fused heterocyclic group of the formula

wherein X¹ and R⁴ are as defined above, and said fused heterocyclicgroup is optionally substituted by 1 or 2 substituents selected from thegroup consisting of a halogen atom, cyano, nitro, hydroxy and alkyl.

Preferable examples of a fused heterocyclic group of the formula (A) or(B) include a fused heterocyclic group of the formula

wherein R⁴ and R⁵ are as defined above, and said fused heterocyclicgroup is optionally substituted by 1 or 2 substituents selected from thegroup consisting of a halogen atom, cyano, nitro, hydroxy and alkyl.

Other preferable examples of a fused heterocyclic group of the formula(A) or (B) include a fused heterocyclic group of the formula

wherein X¹ and R⁴ are as defined above, and said fused heterocyclicgroup is optionally substituted by 1 or 2 substituents selected from thegroup consisting of a halogen atom, cyano, nitro, hydroxy and alkyl.

Examples of a group of the formula (C) include a group of the formula

wherein X², R⁶ and R⁷ are as defined above.

Preferable examples of a group of the formula (C) include a group of theformula

wherein R⁶, R⁷ and R⁸ are as defined above.

In the above formulas, R⁶, R⁷ and Re are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom and amino,    -   (g) alkenyl,    -   (h) alkynyl,    -   (i) aryl,    -   (j) formyl,    -   (k) carboxy,    -   (l) carbamoyl, or    -   (m) a 5- to 10-membered aromatic heterocyclic group (e.g.,        pyridyl, triazolyl) optionally substituted by alkyl.

Examples of a group of the formula (D) or (E) include a group of theformula

wherein R⁶ is as defined above. R⁶ is preferably a hydrogen atom, ahalogen atom, nitro or amino.

Preferably, R³ is 3-pyridyl optionally substituted by 1 or 2substituents selected from the group consisting of

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) amino,    -   (f) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkylamino,        dialkylamino and hydroxy,    -   (g) alkenyl,    -   (h) aryl,    -   (i) cycloalkyl,    -   (j) alkoxy,    -   (k) alkylamino,    -   (l) dialkylamino,    -   (m) phenylamino optionally substituted by 1 to 3 halogen atoms,    -   (n) a cyclic amino group (e.g., 1-piperazinyl, morpholino)        optionally substituted by alkoxycarbonyl,    -   (o) formyl,    -   (p) carbamoyl, and    -   (q) a 5- to 10-membered aromatic heterocyclic group (e.g.,        triazolyl) optionally substituted by alkyl.

More preferably, R³ is a group of the formula

wherein R²² is

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of a halogen atom, alkylamino,        dialkylamino and hydroxy,    -   (e) alkenyl,    -   (f) aryl,    -   (g) cycloalkyl,    -   (h) alkoxy,    -   (i) formyl, or    -   (j) carbamoyl.

Preferably, R²² is

-   -   (a) cyano,    -   (b) nitro,    -   (c) aryl,    -   (d) formyl, or    -   (e) carbamoyl.

Preferably, R³ is 5-pyrimidinyl substituted by 1 or 2 substituentsselected from the group consisting of amino, alkylamino anddialkylamino.

Preferably, R³ is 2-indolyl, 3-indolyl, 5-indolyl or 6-indolyl, eachoptionally substituted by 1 or 2 substituents selected from the groupconsisting of

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of amino, alkoxycarbonylamino,        alkylamino and dialkylamino,    -   (f) alkoxy,    -   (g) formyl,    -   (h) carboxy, and    -   (j) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkoxycarbonyl,        -   (ii) alkylcarbonyl optionally substituted by a substituent            selected from the group consisting of            -   (A) cycloalkyloxy optionally substituted by 1 to 3                alkyl,            -   (B) alkylamino,            -   (C) dialkylamino,            -   (D) a cyclic amino group (e.g., morpholino,                1-piperazinyl) optionally substituted by alkoxycarbonyl,                and            -   (E) a halogen atom,        -   (iii) phenylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of alkyl and            alkoxy,        -   (iv) cycloalkylcarbonyl,        -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group            (e.g, pyridylcarbonyl) optionally substituted by alkyl            optionally substituted by 1 to 3 halogen atoms,        -   (vi) benzylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of a halogen            atom and alkoxy,        -   (vii) arylsulfonyl optionally substituted by alkoxy,        -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1            to 3 substituents selected from the group consisting of            alkyl and oxo (e.g., camphorsulfonyl),        -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group            (e.g., imidazolylsulfonyl) optionally substituted by 1 to 3            alkyl, and        -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl.

More preferably, R³ is 2-indolyl optionally substituted by 1 or 2substituents selected from the group consisting of

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of amino, alkoxycarbonylamino,        alkylamino and dialkylamino,    -   (f) alkoxy,    -   (g) formyl,    -   (h) carboxy, and    -   (j) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkoxycarbonyl,        -   (ii) alkylcarbonyl optionally substituted by a substituent            selected from the group consisting of            -   (A) cycloalkyloxy optionally substituted by 1 to 3                alkyl,            -   (B) alkylamino,            -   (C) dialkylamino,            -   (D) a cyclic amino group (e.g., morpholino,                1-piperazinyl) optionally substituted by alkoxycarbonyl,                and            -   (E) a halogen atom,        -   (iii) phenylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of alkyl and            alkoxy,        -   (iv) cycloalkylcarbonyl,        -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group            (e.g, pyridylcarbonyl) optionally substituted by alkyl            optionally substituted by 1 to 3 halogen atoms,        -   (vi) benzylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of a halogen            atom and alkoxy,        -   (vii) arylsulfonyl optionally substituted by alkoxy,        -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1            to 3 substituents selected from the group consisting of            alkyl and oxo (e.g., camphorsulfonyl),        -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group            (e.g., imidazolylsulfonyl) optionally substituted by 1 to 3            alkyl, and        -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl.

Examples of a group of the formula (F) or (G) include a group of theformula

whereinR²³ is a hydrogen atom or alkyl, andR²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

(a) a hydrogen atom,

(b) cyano, or

(c) nitro.

Examples of a group of the formula (K) include a group of the formula

wherein X⁵, X⁶, X⁷, X⁸ and R¹⁰ are as defined above.

Preferable examples of a group of the formula (K) include a group of theformula

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above.

When R¹⁰ and R¹¹ are bonded to form a 5- or 6-membered ring optionallysubstituted by alkyl or oxo, preferable examples of a group of theformula (K) include a group of the formula

wherein R³¹ is a hydrogen atom or alkyl.

When R¹² and R¹³ are bonded to form a 5- or 6-membered ring, preferableexamples of a group of the formula (K) include a group of the formula

More preferable examples of a group of the formula (K) include a groupof the formula

wherein R^(10a) is

-   -   (a) a hydrogen atom or    -   (b) alkyl, and        R^(11a), R^(13a) and R^(15a) are each independently,    -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) alkylamino,    -   (g) dialkylamino,    -   (h) alkyl optionally substituted by hydroxy, or    -   (i) alkenyl,        R^(10a) and R^(11a) are optionally bonded to form a 5- or        6-membered ring optionally substituted by alkyl or oxo,        provided that R^(10a), R^(11a), R^(13a) and R^(15a) are not        simultaneously hydrogen atom.

Preferably, R³ is a group of the formula

wherein R¹⁶ is

-   -   (a) a hydrogen atom,    -   (b) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of cyano, alkylamino and dialkylamino,    -   (c) alkenyl optionally substituted by carboxy,    -   (d) formyl,    -   (e) carboxy,    -   (f) carbamoyl,    -   (g) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or        hydroxy, or    -   (h) a 5- to 10-membered aromatic heterocyclic group (e.g.,        tetrazolyl, pyrrolyl, oxazolyl, benzimidazolyl, triazolyl)        optionally substituted by alkyl, alkoxycarbonyl, carboxy or        phenyl.

More preferably, R³ is a group of the formula

wherein R^(16a) is

-   -   (a) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of cyano, alkylamino and dialkylamino,    -   (b) alkenyl optionally substituted by carboxy,    -   (c) formyl,    -   (d) carboxy,    -   (e) carbamoyl,    -   (f) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or        hydroxy, or    -   (g) a 5- to 10-membered aromatic heterocyclic group (e.g.,        tetrazolyl, pyrrolyl, oxazolyl, benzimidazolyl, triazolyl)        optionally substituted by alkyl, alkoxycarbonyl, carboxy or        phenyl.

Preferably, R³ is a group of the formula

whereinR¹⁸ is alkyl optionally substituted by 1 to 3 substituents selected fromthe group consisting of a halogen atom and phenyl, andR¹⁹ and R²⁰ are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of        -   (i) a halogen atom,        -   (ii) cyano,        -   (iii) hydroxy,        -   (iv) amino,        -   (v) alkylamino,        -   (vi) dialkylamino, and        -   (vii) a cyclic amino group (e.g., 1-piperazinyl) optionally            substituted by alkyl,    -   (e) alkoxy,    -   (f) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkylcarbonyl optionally substituted by a cyclic amino            group (e.g., morpholino),        -   (ii) alkylsulfonyl, and        -   (iii) carbamoyl,    -   (g) carboxy,    -   (h) alkoxycarbonyl,    -   (i) carbamoyl optionally substituted by alkyl optionally        substituted by amino, alkylamino, dialkylamino or        alkoxycarbonylamino,    -   (j) formyl,    -   (k) a 5- to 10-membered aromatic heterocyclic group (e.g.,        oxazolyl, benzimidazolyl), or    -   (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl        optionally substituted by alkylamino or dialkylamino.

More preferably, R³ is a group of the formula

whereinR^(18a) is alkyl, and

R^(19a) is

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) alkyl optionally substituted by 1 to 3 substituents selected        from the group consisting of        -   (i) a halogen atom,        -   (ii) cyano,        -   (iii) hydroxy,        -   (iv) amino,        -   (v) alkylamino,        -   (vi) dialkylamino, and        -   (vii) a cyclic amino group (e.g., 1-piperazinyl) optionally            substituted by alkyl,    -   (d) alkoxy,    -   (e) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) alkylcarbonyl optionally substituted by a cyclic amino            group (e.g., morpholino),        -   (ii) alkylsulfonyl, and        -   (iii) carbamoyl,    -   (f) carboxy,    -   (g) alkoxycarbonyl,    -   (h) carbamoyl optionally substituted by alkyl optionally        substituted by amino, alkylamino, dialkylamino or        alkoxycarbonylamino,    -   (i) formyl,    -   (j) a 5- to 10-membered aromatic heterocyclic group (e.g.,        oxazolyl, benzimidazolyl), or    -   (k) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl        optionally substituted by alkylamino or dialkylamino.

Preferable examples of compound (I) are as described below.

[Compound I-1]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; orR¹ and R² are optionally bonded to form —O—CH₂—CH(CH₃)— wherein theoxygen atom is bonded to the phenyl ring of the quinolone ring; andR³ is a fused heterocyclic group of the formula

wherein

X¹ is C(R⁵) or N,

R⁴ is a hydrogen atom or C₁₋₆ alkyl, and

R⁵ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) hydroxy,    -   (f) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms,    -   (g) C₂₋₆ alkynyl,    -   (h) C₆₋₁₄ aryl, or    -   (i) C₁₋₆ alkoxy optionally substituted by 1 to 3 halogen atoms,        when X¹ is C(R⁵), R⁴ and R⁵ are optionally bonded to form        —CH₂—O—(C═O)— wherein the carbonyl is bonded to the phenyl ring        of the quinolone ring,        said fused heterocyclic group is optionally substituted by 1 or        2 substituents selected from the group consisting of a halogen        atom, cyano, nitro, hydroxy and C₁₋₆ alkyl,        or a salt thereof.

[Compound I-2]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; orR¹ and R² are optionally bonded to form —O—CH₂—CH(CH₃)— wherein theoxygen atom is bonded to the phenyl ring of the quinolone ring; andR³ is a group of the formula

wherein

X² is C(R⁸) or N, and

R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents        selected from the group consisting of a halogen atom and amino,    -   (g) C₂₋₆ alkenyl,    -   (h) C₂₋₆ alkynyl,    -   (i) C₆₋₁₄ aryl,    -   (j) formyl,    -   (k) carboxy,    -   (l) carbamoyl, or    -   (m) a 5- to 10-membered aromatic heterocyclic group (e.g.,        pyridyl, triazolyl) optionally substituted by C₁₋₆ alkyl,        or a salt thereof.

[Compound I-3]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

wherein

X³ and X⁴ are N, or X³ is N and X⁴ is CH, or X³ is CH and X⁴ is N, and

R⁶ is a hydrogen atom, a halogen atom, nitro or amino,or a salt thereof.

[Compound I-4]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

or a salt thereof.

[Compound I-5]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; orR¹ and R² are optionally bonded to form —O—CH₂—CH (CH₃)— wherein theoxygen atom is bonded to the phenyl ring of the quinolone ring; andR³ is a group of the formula

wherein R²² is

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents        selected from the group consisting of a halogen atom, C₁₋₆        alkylamino, di(C₁₋₆ alkyl)amino and hydroxy,    -   (e) C₂₋₆ alkenyl,    -   (f) C₆₋₁₄ aryl,    -   (g) C₃₋₈ cycloalkyl,    -   (h) C₁₋₆ alkoxy,    -   (i) formyl, or    -   (j) carbamoyl,        or a salt thereof.

[Compound I-6]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; orR¹ and R² are optionally bonded to form —O—CH₂—CH(CH₃)— wherein theoxygen atom is bonded to the phenyl ring of the quinolone ring; andR³ is a group of the formula

wherein R²² is

-   -   (a) cyano,    -   (b) nitro,    -   (c) C₆₋₁₄ aryl,    -   (d) formyl, or    -   (e) carbamoyl,        or a salt thereof.

[Compound I-7]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is 5-pyrimidinyl substituted by 1 or 2 substituents selected from thegroup consisting of amino, C₁₋₆ alkylamino and di(C₁₋₆ alkyl)amino,or a salt thereof.

[Compound I-8]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is 2-indolyl optionally substituted by 1 or 2 substituents selectedfrom the group consisting of

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) nitro,    -   (d) hydroxy,    -   (e) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents        selected from the group consisting of amino, C₁₋₆        alkoxy-carbonylamino, C₁₋₆ alkylamino and di(C₁₋₆ alkyl)amino,    -   (f) C₁₋₆ alkoxy,    -   (g) formyl,    -   (h) carboxy, and    -   (j) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) C₁₋₆ alkoxy-carbonyl,        -   (ii) C₁₋₆ alkyl-carbonyl optionally substituted by a            substituent selected from the group consisting of            -   (A) C₃₋₈ cycloalkyloxy optionally substituted by 1 to 3                C₁₋₆ alkyl,            -   (B) C₁₋₆ alkylamino,            -   (C) di(C₁₋₆ alkyl)amino,            -   (D) a cyclic amino group (e.g., morpholino,                1-piperazinyl) optionally substituted by C₁₋₆                alkoxy-carbonyl, and            -   (E) a halogen atom,        -   (iii) phenylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of C₁₋₆            alkyl and C₁₋₆ alkoxy,        -   (iv) C₃₋₈ cycloalkyl-carbonyl,        -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group            (e.g., pyridylcarbonyl) optionally substituted by C₁₋₆ alkyl            optionally substituted by 1 to 3 halogen atoms,        -   (vi) benzylcarbonyl optionally substituted by 1 to 3            substituents selected from the group consisting of a halogen            atom and C₁₋₆ alkoxy,        -   (vii) C₆₋₁₄ arylsulfonyl optionally substituted by C₁₋₆            alkoxy,        -   (viii) C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfonyl optionally            substituted by 1 to 3 substituents selected from the group            consisting of C₁₋₆ alkyl and oxo (e.g., camphorsulfonyl),        -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group            (e.g., imidazolylsulfonyl) optionally substituted by 1 to 3            C₁₋₆ alkyl, and        -   (x) —C(═N—CN) —SR⁹ wherein R⁹ is C₁₋₆ alkyl,            or a salt thereof.

[Compound I-9]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

whereinR²³ is a hydrogen atom or C₁₋₆ alkyl, andR²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,    -   (b) cyano, or    -   (c) nitro,        or a salt thereof.

[Compound I-10]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

whereinR²⁸ is a hydrogen atom or hydroxy, andR²⁹ is a hydrogen atom or C₁₋₆ alkyl,or a salt thereof.

[Compound I-11]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

whereinR¹⁰, R¹² and R¹⁴ are each independently,

-   -   (a) a hydrogen atom or    -   (b) C₁₋₆ alkyl, and        R¹¹, R¹³ and R¹⁵ are each independently,    -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) C₁₋₆ alkylamino,    -   (g) di(C₁₋₆ alkyl)amino,    -   (h) C₁₋₆ alkyl optionally substituted by hydroxy, or    -   (i) C₂₋₆ alkenyl, or        R¹⁰ and R¹¹ are optionally bonded to form —(C═O)—NH—, —C(R³¹)═N—        or —N═N— wherein R³¹ is a hydrogen atom or C₁₋₆ alkyl, and the        nitrogen atom is bonded to the phenyl ring of the fused ring, or        R¹² and R¹³ are optionally bonded to form —(CH₂)₄—,        or a salt thereof.

[Compound I-12]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

wherein R^(10a) is

-   -   (a) a hydrogen atom or    -   (b) C₁₋₆ alkyl, and        R^(11a), R^(13a) and R^(15a) are each independently,    -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) nitro,    -   (e) amino,    -   (f) C₁₋₆ alkylamino,    -   (g) di(C₁₋₆ alkyl)amino,    -   (h) C₁₋₆ alkyl optionally substituted by hydroxy, or    -   (i) C₂₋₆ alkenyl, and        provided that R^(10a), R^(11a), R^(13a) and R^(15a) are not        simultaneously hydrogen atom,        or a salt thereof.

[Compound I-13]

A compound of the formula (I) whereinR is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

wherein R³¹ is a hydrogen atom or C₁₋₆ alkyl,or a salt thereof.

[Compound I-14]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

wherein R^(16a) is

-   -   (a) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents        selected from the group consisting of cyano, C₁₋₆ alkylamino and        di(C₁₋₆ alkyl)amino,    -   (b) C₂₋₆ alkenyl optionally substituted by carboxy,    -   (c) formyl,    -   (d) carboxy,    -   (e) carbamoyl,    -   (f) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or        hydroxy, or    -   (g) a 5- to 10-membered aromatic heterocyclic group (e.g.,        tetrazolyl, pyrroryl, oxazolyl, benzimidazolyl, triazolyl)        optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,        carboxy or phenyl,        or a salt thereof.

[Compound I-15]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

whereinR^(18a) is C₁₋₆ alkyl, and

R^(19a) is

-   -   (a) a halogen atom,    -   (b) cyano,    -   (c) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents        selected from the group consisting of        -   (i) a halogen atom,        -   (ii) cyano,        -   (iii) hydroxy,        -   (iv) amino,        -   (v) C₁₋₆ alkylamino,        -   (vi) di(C₁₋₆ alkyl)amino, and        -   (vii) a cyclic amino group (e.g., 1-piperazinyl) optionally            substituted by C₁₋₆ alkyl,    -   (d) C₁₋₆ alkoxy,    -   (e) amino optionally substituted by 1 or 2 substituents selected        from the group consisting of        -   (i) C₁₋₆ alkyl-carbonyl optionally substituted by a cyclic            amino group (e.g., morpholino),        -   (ii) C₁₋₆ alkylsulfonyl, and        -   (iii) carbamoyl,    -   (f) carboxy,    -   (g) C₁₋₆ alkoxy-carbonyl,    -   (h) carbamoyl optionally substituted by C₁₋₆ alkyl optionally        substituted by amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino or        C₁₋₆ alkoxy-carbonylamino,    -   (i) formyl,    -   (j) a 5- to 10-membered aromatic heterocyclic group (e.g.,        oxazolyl, benzimidazolyl), or    -   (k) —CH═N—OR wherein R²¹ is a hydrogen atom or C₁₋₆ alkyl        optionally substituted by C₁₋₆ alkylamino or di(C₁₋₆        alkyl)amino,        or a salt thereof.

[Compound I-16]

A compound of the formula (I) wherein

R is a hydrogen atom;R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl;R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or achlorine atom; andR³ is a group of the formula

wherein

R³⁰ is

-   -   (a) a hydrogen atom,    -   (b) a halogen atom,    -   (c) cyano,    -   (d) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents        selected from the group consisting of a halogen atom and        hydroxy,    -   (e) C₂₋₆ alkenyl,    -   (f) C₂₋₆ alkynyl,    -   (g) C₁₋₆ alkoxy,    -   (h) formyl, or    -   (i) —CH═N—OH,        or a salt thereof.

Examples of salts of the compound of the formula (I) includepharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compound of the formula (I) are conventional non-toxicsalts and include, for example, a salt with a base or an acid additionsalt such as a salt with an inorganic base, for example, an alkali metalsalt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metalsalt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; asalt with an organic base, for example, an organic amine salt (e.g.,trimethylamine salt, triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid additionsalt (e.g., hydrochloride, hydrobromide, sulfate, hydrogensulfate,phosphate, etc.); an organic carboxylic or sulfonic acid addition salt(e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate,fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.);and a salt with a basic or acidic amino acid (e.g., arginine, asparticacid, glutamic acid, etc.).

Compound (I) can be produced, for example, by a method according to thefollowing reaction schemes.

wherein X, R¹ and R² are as defined above, R³² is alkyl and R³³ isalkyl.

Step a

Compound (1) can be converted to acid halide by reacting compound (1)with a halogenating agent in the presence or absence of a solvent. Thesolvent includes aromatic hydrocarbons such as benzene, toluene andxylene; halogenated hydrocarbons such as dichloromethane, chloroform andcarbon tetrachloride; ethers such as dioxane, tetrahydrofuran anddiethyl ether; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO);and the like. The halogenating agent may be any conventionalhalogenating agents which can convert hydroxy in carboxy group into ahalogen atom, and includes, for example, thionyl chloride, phosphorusoxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphoruspentabromide, and the like. The amounts of compound (1) and thehalogenating agent are not particularly limited, but, in case of usingno solvent, the halogenating agent is usually used in a large excessamount, and in case of using a solvent, the halogenating agent isusually used in an amount of at least 1 mole, preferably 2 to 4 moles,per 1 mole of compound (1). The reaction temperature and the reactionperiod of time are not particularly limited, but the reaction is usuallycarried out at a temperature of from room temperature to about 100° C.for about 30 minutes to about 6 hours.

The obtained acid halide is reacted with magnesium salt of malonic acidmonoalkyl ester to give compound (2). Magnesium salt of malonic acidmonoalkyl ester can be prepared in situ from potassium salt of malonicacid monoalkyl ester such as potassium ethyl malonate in the presence ofmagnesium chloride and a basic compound such as triethylamine. Thereaction can be carried out in a suitable solvent. The solvent used inthe reaction may be any conventional solvents unless they give anyundesirable effect on the reaction, and includes, for example, esterssuch as ethyl acetate; ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme and diglyme; alcohols such as methanol,ethanol and isopropanol; aromatic hydrocarbons such as benzene, tolueneand xylene; aliphatic hydrocarbons such as n-hexane, heptane,cyclohexane and ligroin; amines such as pyridine andN,N-dimethylaniline; halogenated hydrocarbons such as chloroform,dichloromethane and carbon tetrachloride; aprotic polar solvents such asDMF, DMSO and hexamethylphosphoric triamide (HMPA); and a mixture ofthese solvents. The reaction is usually carried out at a temperature offrom about 0° C. to about 150° C., preferably from about 0° C. to about120° C., for about 0.5 to about 20 hours. Potassium salt of malonic acidmonoalkyl ester is usually used in an amount of at least 1 mole,preferably 1 to 2 moles, per 1 mole of compound (1). Magnesium chlorideand the basic compound are usually used in an amount of at least 1 mole,preferably 1 to 2 moles, per 1 mole of compound (1).

Step b

Compound (3) can be prepared by reacting compound (2) with trialkylorthoformate such as trimethyl orthoformate and triethyl orthoformate inacetic anhydride. The reaction is usually carried out at a temperatureof from about 0° C. to about 200° C., preferably from about 0° C. toabout 150° C., for about 0.5 to about 20 hours. Trialkyl orthoformate isusually used in an amount of at least 1 mole, preferably 1 to 10 moles,per 1 mole of compound (2).

Step c

Compound (4) can be prepared by reacting compound (3) with compound (6).

The reaction between compound (3) and compound (6) can be carried out ina suitable solvent. The solvent employed in the reaction may be anyconventional solvents unless they give any undesirable effect on thereaction, and includes, for example, alcohols such as methanol, ethanoland propanol; ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme and diglyme; aromatic hydrocarbons such as benzene, tolueneand xylene; aliphatic hydrocarbons such as n-hexane, heptane,cyclohexane and ligroin; halogenated hydrocarbons such as chloroform,methylene chloride and carbon tetrachloride; aprotic polar solvents suchas DMF, DMSO and HMPA; and the like. The reaction is usually carried outat a temperature of from about 0° C. to about 150° C., preferably fromroom temperature to about 100° C., for about 0.1 to about 15 hours.Compound (6) is usually used in an amount of at least 1 mole, preferably1 to 2 moles, per 1 mole of compound (3).

Step d

Compound (5) can be prepared by cyclization of compound (4).

The cyclization of compound (4) can be carried out in a suitable solventin the presence of a basic compound. The solvent employed in thereaction may be any conventional solvents unless they give anyundesirable effect on the reaction, and includes, for example, etherssuch as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme;aliphatic hydrocarbons such as n-hexane, heptane and ligroin;halogenated hydrocarbons such as chloroform, methylene chloride andcarbon tetrachloride; aprotic polar solvents such as DMF, DMSO and HMPA;and the Like. The basic compound employed in the reaction includesinorganic bases such as metallic sodium, metallic potassium, sodiumhydride, sodium amide, sodium hydroxide, potassium hydroxide, sodiumcarbonate and potassium carbonate, metal alcoholates such as sodiummethylate and sodium ethylate, organic bases such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-benzyltrimethylammoniumhydroxide and tetrabutylammonium hydroxide, and the like. The reactionis usually carried out at a temperature of from about 0° C. to about200° C., preferably from room temperature to about 150° C., for about0.5 to about 15 hours. The basic compound is usually used in an isamount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of thecompound (4).

wherein X, R¹, R², R³ and R³² are as defined above.

Step a

Compound (Ia) can be prepared by reacting compound (5) and compound (7)or compound (8) in an inert solvent or without using any solvents, inthe presence or absence of a basic compound, in the presence of apalladium catalyst.

Examples of inert solvents include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycoldimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbonssuch as benzene, toluene and xylene; alcohols such as methanol, ethanoland isopropanol; ketones such as acetone and methyl ethyl ketone; andaprotic polar solvents such as DMF, DMSO, HMPA and acetonitrile. Theseinert solvents can be used singly or in combinations of two or more.

The palladium catalyst used in the reaction is not particularly limited,but include, for example, tetravalent palladium catalysts such as sodiumhexachloropalladate(IV) tetrahydrate and potassiumhexachloropalladate(IV); divalent palladium catalysts such aspalladium(II) chloride, palladium(II) bromide, palladium(II) acetate,palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium (II),dichlorobis(acetonitrile)palladium(II),dichlorobis(triphenylphosphine)palladium (II), dichlorotetraminepalladium(II), dichloro(cycloocta-1,5-diene)palladium(II), palladium(II)trifluoroacetate, and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane complex (Pd(dppf)Cl₂.CH₂Cl₂);zerovalent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone) dipalladium(0) chloroformcomplex and tetrakis(triphenylphosphine)palladium (0), etc. Thesepalladium catalysts are used singly or in combinations of two or more.

In the reaction, the amount of the palladium catalyst is notparticularly limited, but is typically in the range from 0.000001 to 20moles in terms of palladium relative to 1 mole of compound (5). Theamount of the palladium catalyst is preferably in the range from 0.0001to 5 moles in terms of palladium relative to 1 mole of compound (5).

This reaction advantageously proceeds in the presence of a suitableligand. Examples of ligands of the palladium catalyst include, forexample, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),tri-o-tolylphosphine, bis(diphenylphosphino) ferrocene,triphenylphosphine, tri-t-butylphosphine and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). Theseligands are used singly or in combinations of two or more.

The proportion of the palladium catalyst and ligand is not particularlylimited. The amount of the ligand is about 0.1 to about 100 moles per 1mole of the palladium catalyst, and preferably about 0.5 to about 15moles per 1 mole of the palladium catalyst.

Various known inorganic and organic bases can be used as basiccompounds.

Inorganic bases include, for example, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, cesium hydroxide and lithiumhydroxide; alkali metal carbonates such as sodium carbonate, potassiumcarbonate, cesium carbonate and lithium carbonate; alkali metal hydrogencarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonateand potassium hydrogen carbonate; alkali metals such as sodium andpotassium; phosphates such as sodium phosphate and potassium phosphate;amides such as sodium amide; and alkali metal hydrides such as sodiumhydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such assodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide and potassium t-butoxide, and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), etc.

Such basic compounds can be used singly or in combinations of two ormore. More preferable basic compounds used in the reaction includealkali metal carbonates such as sodium carbonate, potassium carbonate,cesium carbonate and lithium carbonate.

The basic compound is usually used in an amount of 0.5 to 10 moles per 1mole of compound (5), and preferably 0.5 to 6 moles per 1 mole ofcompound (5).

Compound (7) or compound (8) is usually used in an amount of at least 1mole per 1 mole of compound (5), and preferably about 1 to about 5 molesper 1 mole of compound (5).

The reaction can be conducted under normal pressure, under inert gasatmosphere including nitrogen, argon, etc., or under increased pressure.

The reaction proceeds usually from room temperature to about 200° C.,and preferably from room temperature to about 150° C., and is usuallycompleted in about 1 to about 30 hours. The reaction is also achieved byheating at about 100° C. to about 200° C. for about 5 minutes to about 1hour using a microwave reactor.

Step b

Compound (Ib) can be prepared by hydrolysis of compound (Ia).

The hydrolysis of compound (Ia) can be carried out under the conditionsof conventional hydrolysis, for example, in the presence of a basiccompound such as sodium hydroxide, potassium hydroxide, barium hydroxideor potassium carbonate; a mineral acid such as sulfuric acid,hydrochloric acid or nitric acid; or an organic acid such as acetic acidor an aromatic sulfonic acid, in a solvent including water, alcoholssuch as methanol, ethanol and isopropanol; ketones such as acetone andmethyl ethyl ketone; ethers such as dioxane and ethylene glycol diethylether; acetic acid; or a mixture thereof. The reaction is usuallycarried out at a temperature of from room temperature to about 200° C.,preferably from room temperature to about 150° C., for about 0.1 toabout 30 hours.

Reaction Scheme III Preparation of Boronate and Boronic Acid

wherein R³ is as defined above, and Z is a bromine atom or an iodineatom.

Step a

Compound (7) can be prepared by reacting compound (9) withbis(pinacolato)diboron (10) in an inert solvent in the presence of apalladium catalyst and a basic compound.

Examples of inert solvents and palladium catalyst are same as thosedescribed in Step a in Reaction Scheme II.

The basic compound employed in the reaction includes potassium acetate,triethylamine, N-methylmorpholin, sodium carbonate, potassium carbonate,cesium carbonate, lithium carbonate, potassium phosphate and sodiumhydrogen carbonate.

In the reaction, the amount of the palladium catalyst is notparticularly limited, but is typically in the range from 0.000001 to 20moles in terms of palladium relative to 1 mole of compound (9). Theamount of the palladium catalyst is preferably in the range from 0.0001to 5 moles in terms of palladium relative to 1 mole of compound (9).

The basic compound is usually used in an amount of 0.5 to 10 moles per 1mole of compound (9), and preferably 0.5 to 6 moles per 1 mole ofcompound (9).

Bis(pinacolato)diboron (10) is usually used in an amount of at least 1mole per 1 mole of compound (9), and preferably about 1 to about 5 molesper 1 mole of compound (9).

The reaction can be conducted under normal pressure, under inert gasatmosphere including nitrogen, argon, etc., or under increased pressure.

The reaction proceeds usually from room temperature to about 200° C.,and preferably from room temperature to about 150° C., and is usuallycompleted in about 1 to about 30 hours.

Step b

Compound (8) can be prepared by reacting compound (9) with trialkylborate such as trimethyl borate, triethyl borate, tri(isopropyl) borateand tri(n-butyl) borate in an inert solvent in the presence ofn-butyllithium or lithium diisopropylamide.

Examples of inert solvents are same as those described in Step a inReaction Scheme II.

The trialkyl borate is usually used in an amount of at least 1 mole per1 mole of compound (9), and preferably about 1 to about 5 moles per 1mole of compound (9).

n-Butyllithium or lithium diisopropylamide is usually used in an amountof at least 1 mole per 1 mole of compound (9), and preferably about 1 toabout 5 moles per 1 mole of compound (9).

The reaction is usually carried out at a temperature of from about −70°C. to about 0° C. for about 0.1 to about 15 hours.

Compound (I) of the present invention can easily be converted into asalt thereof by treating with a pharmaceutically acceptable acid orbase. The acid includes inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid and hydrobromic acid and organic acidssuch as oxalic acid, maleic acid, fumaric acid, malic acid, tartaricacid, citric acid, benzoic acid, lactic acid, methanesulfonic acid andpropionic acid. The base includes sodium hydroxide, potassium hydroxide,calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, andthe like.

The compound thus obtained can easily be isolated and purified byconventional methods, such as, for example, extraction with solvents,dilution method, recrystallization, column chromatography andpreparative thin layer chromatography.

Compound (I) shows an excellent antimicrobial activity againstmycoplasma, Pseudomonas aeruginosa, anaerobic bacteria, resistant cellsagainst various antimicrobials, clinically isolated bacteria, and gramnegative and gram positive bacteria such as Clostridium difficile,Enterococcus faecalis and Staphylococcus pyogenes and hence is useful asan antimicrobial agent for the treatment of diseases induced by thesemicroorganisms. Compound (I) also shows low toxicity and less sideeffects and is characteristic in good absorbability and in sustainedactivity.

Since compound (I) shows an excellent antimicrobial activity againstClostridium difficile, it is useful for the prevention or treatment ofintestinal infections including antibiotics-associated diarrhea (AAD)such as Clostridium difficile-associated diarrhea (CDAD).

The compounds of the present invention are usually used in the form of ausual pharmaceutical preparation. The pharmaceutical preparation can beprepared in admixture with conventional pharmaceutically acceptablediluents or carriers, such as fillers, bulking agents, binding agents,wetting agents, disintegrators, surfactants and lubricating agents. Thepharmaceutical preparation includes various preparations suitable fortreatment of the diseases, for example, tablets, pills, powders,solutions, suspensions, emulsions, granules, capsules, suppositories,injections such as solutions and suspensions, and the like. In thepreparation of tablets, there may be used any conventional carriers, forexample, excipients such as lactose, white sugar, sodium chloride,glucose, urea, starches, calcium carbonate, kaolin, crystallinecellulose and silicate, binding agents such as water, ethanol, propanol,simple syrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphateand polyvinylpyrrolidone, disintegrators such as dry starch, sodiumalginate, agar powder, laminaran powder, sodium hydrogen carbonate,calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodiumlauryl sulfate, stearic monoglyceride, starches and lactose,disintegration inhibitors such as white sugar, stearin, cacao butter andhydrogenated oils, absorption promoters such as quaternary ammoniumsalts and sodium lauryl sulfate, wetting agents such as glycerin andstarches, adsorbents such as starches, lactose, kaolin, bentonite andcolloidal silicates, lubricants such as purified talc, stearates, boricacid powder and polyethylene glycol, and the like. The tablets may alsobe coated with conventional coating agents, for example, may be in theform of a sugar coated tablet, a gelatin-coated tablets, an entericcoating tablet, a film coating tablet, or a double or multiple layerstablet. In the preparation of pills, there may be used conventionalcarriers, including excipients such as glucose, lactose, starches, cacaobutter, hydrogenated vegetable oils, kaolin and talc, binding agentssuch as gum arabic powder, tragacanth powder, gelatin and ethanol,disintegrators such as laminaran and agar, and the like. In thepreparation of suppositories, there may be used conventional carriers,such as, for example, polyethylene glycol, cacao butter, higheralcohols, higher alcohol esters, gelatin and semi-synthesizedglycerides. In the preparation of injections, the solutions, emulsionsor suspensions of the compounds are sterilized and are preferably madeisotonic with the body liquid. These solutions, emulsions andsuspensions are prepared by admixing the active compound with aconventional diluent, such as water, aqueous lactic acid solution, ethylalcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol or polyoxyethylene sorbitan fatty acid esters. Thepreparations may also be incorporated with sodium chloride, glucose orglycerin in an amount sufficient to make them isotonic with the bodyliquid. The preparations may also be incorporated with conventionalsolubilizers, buffering agents, anesthetizing agents, and further, withcoloring agents, preservatives, perfumes, flavors, sweetening agents,and other medicaments. The preparations in the form of a paste, cream orgel may be prepared by using as a diluent such as white petrolatum,paraffin, glycerin, cellulose derivatives, polyethylene glycol,silicone, bentonite, or the like. When the compound of the activeingredient precipitates in the injection, an acid such as, for example,methanesulfonic acid, propionic acid, hydrochloric acid, succinic acidor lactic acid may be added to the injection as required to preserve theinjection in a stable solution.

Compound (I) may be contained in any amount in the preparations, and areusually contained in an amount of from 1 to 70% by weight based on thewhole weight of the preparations.

The pharmaceutical preparations of the present invention can beadministered in any methods. Suitable method for administration may beselected in accordance with the preparation form, age and sex ofpatients, severity of the 25 diseases, and the like. For instance,tablets, pills, solutions, suspensions, emulsions, granules and capsulesare administered in oral route. In case of injection, it is administeredintravenously in a single form or together with an auxiliary liquid suchas glucose or amino solution. The injections may also be administered inintramuscular, intracutaneous, subcutaneous, or intraperitoneal route.Suppositories are administered in intrarectal route.

The dosage of the pharmaceutical preparations of the present inventionmay vary according to administration methods, age and sex of patients,severity of the diseases, and the like, usually in the range of about0.1 to about 100 mg, more preferably in the range of about 0.1 to about50 mg, of compound (I) per 1 kg body weight of the patient per day. Thepreparation is usually administered by dividing into 2 to 4 times perday.

The present invention is illustrated by the following Examples,Experimental Examples and Preparation Examples. It is to be understoodthat the present invention is not limited to these Examples,Experimental Examples or Preparation Examples and various changes andmodifications can be made without departing from the scope and spirit ofthe present invention.

EXAMPLES

In our work, Suzuki coupling was employed as key reaction to constructour final products. For the coupling, the correspondingiodo-intermediates could be prepared through well-known methods thatwere wildly used to synthesis of quinolones before (General Scheme I).

Example 1 Synthesis of Intermediate 5a (R²=Me)

1.1. Compound 2: A mixture of compound 1 (2 g, 6.71 mmol) and thionylchloride (9.8 mL) was refluxed for 3 hr, and then concentrated to giveacid chloride. To the residue was added dry EtOAc (10 mL) and then themixture was concentrated.

A mixture of potassium ethyl malonate (1.6 g, 9.40 mmol) and MgCl₂ (1.91g, 20.13 mmol) in dry EtOAc was stirred for 30 min below 50° C. To themixture was added Et₃N (2.83 mL, 20.13 mmol) below 50° C. Then, themixture was refluxed for 1 hr. To the mixture was added dropwise asolution of the acid chloride in dry EtOAc (10 mL) at 50-70° C. and thenthe mixture was refluxed for 1.5 hr. Water (30 mL) and 5 N HCl (30 mL)were added to the reaction mixture under ice-cooling. The EtOAc solutionwas washed with water, dried and concentrated to give compound 2 as ayellow oil, which was used in the next step without purification.

1.2. Compound 3: A mixture of compound 2 (11 g, 29.88 mmol), triethylorthoformate (7.47 mL, 44.82 mmol) and acetic anhydride (6.77 mL, 71.72mmol) was heated at 150° C. for 1 hr, and then concentrated to givecompound 3, which was used in the next step without purification.1.3. Compound 4: To compound 3 (obtained above) were added EtOH (50 mL)and cyclopropylamine (2.48 mL, 35.86 mmol). The mixture was stirred for30 min and concentrated to give compound 4, which was used in the nextstep without purification.1.4. Intermediate 5a: Compound 4 (obtained above) was dissolved in dryDMSO (100 mL). K₂CO₃ (16.52 g, 119.53 mmol) was added to the solution.The reaction mixture was stirred at 100° C. for 1 hr. When TLC(EtOAc/dipropyl ether=1/1) indicated the reaction was completed, themixture was cooled to room temperature, poured into water, and extractedwith EtOAc. The organic layer was washed with brine, dried andconcentrated to give a yellow solid which was recrystallized from EtOAc.Intermediate 5a was obtained as a white solid in 75% overall yield. ¹HNMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 4.29-4.14(m, 3H), 2.96 (s, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.14 (q, J=7.0 Hz, 2H),0.87-0.76 (m, 2H).

The following compounds were synthesized according to General Scheme I.

Example 2

Intermediate 5b (R²=OMe): ¹H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.69(d, J=7.7 Hz, 1H), 4.23 (dd, J=14.0, 6.9 Hz, 2H), 4.03 (s, 1H), 3.80 (s,3H), 1.28 (t, J=7.0 Hz, 3H), 1.09 (d, J=6.2 Hz, 2H), 0.97 (m, 2H).

Example 3

Intermediate 5c (R²=Cl): ¹H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 7.81 (d,J 7.6 Hz, 1H), 4.23 (m, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.21-1.08 (dd,J=7.1, 2.2 Hz, 2H), 0.99-0.92 (m, 2H).

Example 4

Intermediate 5d: ¹H NMR (400 MHz, CDCl₃) δ 8.59-8.51 (d, J=3.1 Hz, 1H),8.03-7.92 (d, J=7.5 Hz, 1H), 4.98-4.73 (dddd, J=62.9, 6.3, 4.9, 3.4 Hz,1H), 4.44-4.34 (q, J=7.1 Hz, 211), 3.91-3.83 (dt, J=8.6, 5.4 Hz, 1H),2.95-2.88 (s, 3H), 1.59-1.48 (m, 111), 1.45-1.38 (t, J=7.1 Hz, 3H),1.35-1.18 (m, 1H).

Example 5

Intermediate 5e: ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.43 (d, J=2.0 Hz, 1H),7.94-7.86 (d, J=7.6 Hz, 1H), 4.90-4.65 (dddd, J=62.7, 6.0, 5.1, 3.3 Hz,1H), 4.37-4.28 (q, J=7.1 Hz, 2H), 3.80-3.76 (s, 3H), 3.75-3.69 (dt,J=8.7, 5.5 Hz, 1H), 1.61-1.47 (m, 2H), 1.46-1.30 (m, 4H).

Example 6

Intermediate 5f: ¹H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.48 (d, J=8.16Hz, 1H), 4.79 (q, J=6.65 Hz, 1H), 4.62 (dd, J=1.82, 11.36 Hz, 1H), 4.44(dd, J=2.20, 11.36 Hz, 1H), 4.23 (qd, J=2.95, 7.09 Hz, 2H), 1.40 (d,J=6.65 Hz, 3H), 1.28 (t, J=7.09 Hz, 3H).

General Scheme II outlined the preparation of required boronic acids andboronates. They are readily prepared through general methods.

Example 7 Synthesis of Boronic Acid 7

Reaction reagents and conditions: a. 1) NaH, THF, r.t.; 2) nBui,B(OiPr)₃, −70° C. to 0° C.7.1 Boronic acid 7: To a solution of compound 6 (10 g, 44.44 mmol) indry tetrahydrofuran (350 mL) was added sodium hydride (2 g, 66.66 mmol,80% dispersion) at 0° C. After the mixture was stirred at roomtemperature for 30 min, the mixture was cooled below −60° C. in a dryice/acetone bath, and n-butyllithium (70 mL, 112 mmol, 1.6 M in hexane)was added over 30 min. The mixture was kept stirring for another 30 min,then triisopropyl borate (40 mL, 177 mmol) was added dropwise. Thereaction mixture was stirred for 10 min, and then warmed to 0° C. slowlyin an ice bath. HCl (5 N) was added to the mixture to adjust pH=3-4, andthe mixture was stirred for 20 min. Aq. NaOH was added to the mixture toadjust pH=10. After filtration, the organic layer was separated. Theaqueous layer was extracted with a mixture of ethyl acetate/THF (4/1;2×120 mL) and EtOAc (100 mL). The aqueous layer was adjusted to pH=5-6with HCl. The precipitate thus formed was collected by filtration anddried to give boronic acid 7 (3.5 g, 41%) as a white solid.

Example 8 Synthesis of Boronate 10

8.1 Compound 9: 2-Aminonicotinonitrile 8 (100 g, 0.839 mol) wasdissolved in HOAc (800 mL). To the solution was added Na₂CO₃ (88.97 g,0.839 mol). Then, Br₂ (46.4 mL, 0.923 mol) was added dropwise. Thereaction mixture was stirred at room temperature for 50 min. To themixture was added water (600 mL). The mixture was cooled to about 5° C.The precipitate thus formed was collected by filtration and dried togive compound 9 (207 g, 96%).8.2 Boronate 10: Compound 9 (50 g, 0.224 mol), bis(pinacolato)diboron(85.6 g, 0.337 mol), KOAc (44.1 g, 0.449 mol) and Pd(dppf)Cl₂.CH₂Cl₂(2.77 g, 3.4 mmol) were charged into a flask. Dioxane (400 mL) wasadded. The reaction mixture was stirred at 100° C. for 2 hr under Ar.When LC-MS indicated that the reaction was completed, the mixture wascooled to room temperature. The mixture was filtered through diatomite,concentrated, diluted with a mixture of ethyl acetate and hexane in 3/1ratio (1000 mL), filtered through silica gel (300-400 mesh),concentrated, crystallized and dried to give boronate 10 (32 g, 66%) asa white solid.

Example 9 Synthesis of Boronate 13

9.1 Compound 12: 3-Chloropyridin-2-amine (100 g, 0.778 mol) wasdissolved in acetic acid (1200 mL). To the solution was added Na₂CO₃(82.4 q, 0.778 mol). Then, Br: (39.1 mL, 0.856 mmol) was added dropwise.After addition, the reaction mixture was stirred at room temperature for30 min. To the mixture was added water (800 mL). The mixture was cooledto about 5° C. The resulting solid was collected by filtration and driedto give compound 12 (147 g, 91%) as a white solid.9.2 Boronate 13: Compound 12 (4 g, 17.2 mmol), bis(pinacolato)diboron(4.79 g, 18.8 mmol), KOAc (3.37 g, 34.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂(0.210 g, 0.25 mmol) were charged into a flask. Dioxane (80 mL) wasadded. The mixture was stirred at 85° C. for 2 hr under Ar. When LC-MSindicated that the reaction was completed, the mixture was cooled toroom temperature. The mixture was filtered through diatomite andconcentrated. The residue was diluted with ethyl acetate and hexane(3/1, 100 mL), filtered through silica gel (300-400 mesh), concentratedand crystallized by n-hexane to give boronate 13 (3.4 g, 78%) as a whitesolid.

Example 10 Synthesis of Compound I-2

10.1 Compound 16: Intermediate 5a (30 g, 65 mmol), boronic acid 7 (17 g,71.6 mmol) and K₂CO₃ (27, 195 mmol) were charged into a flask. Dioxane(600 mL) and water (60 mL) were added. The solution was deoxygenatedwith N₂ for 15 min. Pd(dppf)Cl₂.CH₂Cl₂ (2.8 g, 3.24 mmol) was added tothe mixture. The reaction mixture was stirred at 85° C. overnight. Whenthe reaction was completed, the reaction mixture was cooled to roomtemperature. The precipitate was filtered, dissolved in water, filtered,triturated with EtOH, filtered and dried to give compound 16 (16 g, 57%)as an off-white solid. The obtained compound was pure enough for use.

The organic filtrate was concentrated. To the residue were added water,dichloromethane and EtOAc. The precipitate thus formed was collected byfiltration and dissolved in HCl (5 N). After filtration to remove Pdresidue, the filtrate was basified with aq. NaOH (pH=7-8). Theprecipitate was collected by filtration and dried to give compound 16 (3g, 11%) as an off-white solid.

10.2 Compound I-2: Compound 16 (33 g, 76.1 mmol) was suspended in EtOH(300 mL). Aq. NaOH (4 N, 100 mL) was added to the suspension, and themixture was stirred at 60° C. for 2 hr. 200 mL of EtOH was evaporatedunder reduced pressure. To the residue was added HCl (5 N) to adjustpH=4. The resulting precipitate was filtered, triturated with EtOH,filtered and dried to give compound 1-2 (30 g, 97%) as an off-whitesolid. m.p. >300° C. ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.39 (s,1H), 8.92 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.01 (m, 2H), 6.67 (d,J=9.4 Hz, 1H), 4.42 (s, 1H), 2.68 (s, 3H), 1.27 (d, J=6.4 Hz, 2H),1.12-1.03 (m, 2H). ¹C NMR (101 MHz, DMSO) δ 176.92, 165.25, 162.85,158.16, 155.72, 152.71, 150.92, 149.62, 139.29, 138.79, 137.62, 133.70,133.52, 131.80, 127.47, 127.38, 123.75, 123.42, 113.89, 108.05, 107.81,107.29, 41.29, 20.64, 20.62, 10.62. HPLC-MS m/z 406 (MH⁺). Anal. Calcdfor C₂₂H₁₆FN₃O₄: C, 65.18; H, 3.98; N, 10.37. Found: C, 63.50; H, 4.00;N, 9.91.

Example 11 Synthesis of Compound 2-18

11.1 Compound 17: Boronate 10 (14 g, 56.1 mmol), intermediate 5a (20 g,46.7 mmol), Cs₂CO₃ (15.22 g, 46.7 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (0.98 g,1.2 mmol) were charged into a flask. Dioxane (500 mL) and water (5 mL)were added. The mixture was stirred at 110° C. overnight under Ar. Themixture was cooled to room temperature. The mixture was filtered, andthe solid was washed with dioxane and ethyl acetate. The solid wasdissolved in hot CH₂Cl₂ (1200 mL), and the solution was filtered throughdiatomite. The operation was repeated twice. The organic layers werecombined and concentrated. To the residue was added ethyl acetate (200mL). The solid was collected by filtration, washed with ethyl acetate(60 mL) and dried to give compound 17 (17.6 g, 90%) as a white solid.11.2 Compound 2-18: Compound 17 (43 g, 0.101 mol) was dissolved in THFand EtOH (1/1, 500 mL). To the solution was added NaOH (60 mL, 4 N). Themixture was stirred at room temperature for 2 hr. HCl (63 mL, 4 N) wasadded to acidify the mixture (pH=3-4). The solid was collected byfiltration, washed with EtOH (100 mL) and dried to give compound 2-18(35.7 g, 99%) as a white solid. m.p. >300° C. ¹H NMR (400 MHz, DMSO) δ14.65 (s, 1H), 8.89 (s, 1H), 8.32-8.23 (m, 1H), 8.08 (d, J=2.09 Hz, 1H),7.94 (d, J=8.87 Hz, 1H), 7.28 (s, 2H), 4.40 (tt, J=3.74, 7.17 Hz, 1H),2.67 (s, 3H), 1.31-1.19 (m, 2H), 1.10-0.99 (m, 2H). ¹³C NMR (101 MHz,DMSO) δ 176.95, 176.92, 165.32, 159.60, 158.29, 155.86, 154.07, 152.67,143.59, 139.32, 133.39, 133.22, 131.73, 127.13, 127.05, 116.93, 116.52,107.96, 107.71, 107.27, 89.15, 41.32, 20.64, 20.62, 13.0.65. HPLC-MS m/z379 (MH⁺). Anal. Calcd for C₂₀H₁₅FN₄O₃: C, 63.49; H, 4.00; N, 14.81.Found: C, 62.04; H, 4.20; N, 13.97.

Example 12 Synthesis of Compound 3-11

12.1 Compound 18: Boronate 13 (20 g, 75.4 mmol), intermediate 5a (24.1g, 58.03 mmol), Cs₂CO₃ (26.5 g, 81.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (1.42g, 1.7 mmol) were charged into a flask. Dioxane (400 mL) and water (4mL) were added. The mixture was stirred at 100° C. overnight under Ar.The mixture was cooled to room temperature. The mixture was filtered,and the solid was washed with dioxane and ethyl acetate. The solid wasdissolved in hot CH₂Cl₂ (1200 mL), and the solution was filtered throughdiatomite. The operation was repeated twice. The organic layers werecombined and concentrated. To the residue was added ethyl acetate (200mL). The solid was collected by filtration, washed with ethyl acetate(60 mL) and dried to give compound 18 (21 g, 85%) as a white solid.12.2 Compound 19: Compound 18 (39 g, 91.91 mmol) was dissolved in THFand EtOH (1/1, 600 mL). To the mixture was added NaOH (4 N, 60 mL). Themixture was stirred at room temperature for 2 hr. HCl (4 N, 62 mL) wasadded to acidify the solution (pH=3-4). The solid was collected byfiltration, washed with EtOH (100 mL) and dried to give compound 19 (34g, 98%) as a white solid.12.3 Compound 3-11: Chloroacetaldehyde (40% in water, 80 mL) was addedto a solution of compound 19 (34 g, 91.9 mmol) in EtOH (600 mL). Themixture was refluxed for 3 hr. When LC-MS indicated that the reactionwas completed, the mixture was cooled to 5° C. and filtered. The solidwas dried to give compound 3-11 (21 g). The mother liquid was basified(pH=7-8) with aq. NaOH. The precipitate was collected by filtration,washed with EtOH and dried to give compound 3-11 (11.5 g) as a whitesolid. In total, 32.5 g of compound 3-11 was obtained in 93% yield.m.p.: 307-311° C. ¹H NMR (400 MHz, DMSO) δ 14.53 (s, 1H), 8.98-8.84 (m,2H), 8.28 (d, J=1.16 Hz, 1H), 7.98 (d, J=8.83 Hz, 1H), 7.90 (d, J=0.89Hz, 1H), 7.77 (s, 1H), 4.43 (tt, J=3.70, 7.10 Hz, 1H), 3.50-3.36 (m,1H), 2.72 (s, 3H), 1.26 (d, J=6.80 Hz, 2H), 1.07 (d, J=18.24 Hz, 2H).¹³C NMR (101 MHz, DMSO) δ 176.91, 176.88, 165.23, 158.22, 155.77,152.84, 139.98, 139.17, 139.16, 132.44, 132.15, 131.98, 131.54, 127.86,127.78, 127.38, 120.72, 118.97, 116.37, 108.15, 107.91, 107.37, 41.38,20.54, 20.52, 10.72. HPLC-MS: m/z 412 (MH⁺). Anal. Calcd forC₂₁H₁₅ClFN₃O₃: C, 61.25; H, 3.67; N, 10.20. Found: C, 58.59; H, 3.86; N,9.76.

Compounds listed in the following Tables were synthesized according toGeneral Scheme III.

TABLE 1

Compound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 1-1 

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 12.41 (s, 1H),8.82 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.99(d, J = 9.1 Hz, 1H), 6.66 (dd, J = 9.5, 1.6 Hz, 1H), 4.24 (s, 1H), 3.42(s, 3H), 1.19 (d, J = 7.2 Hz, 4H). 422 98% 1-2 

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.39 (s, 1H),8.92 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.01 (m, 2H), 6,67 (d, J = 9.4Hz, 1H), 4,42 (s, 1H), 2.68 (s, 3H), 1.27 (d, J = 6.4 Hz, 2H), 1.12-1.03(m, 2H). 406 98% 1-3 

OMe

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 12.41 (s, 1H), 8.85 (d, J = 1.3Hz, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 8.00 (d,J = 9.1 Hz, 1H), 6.77-6.54 (m, 1H), 5.24-4.97 (m, 1H), 4.29-4.10 (m,1H), 3.44 (s, 3H), 1.89-1.59 (m, 2H). 440 98% 1-4 

Me

¹H NMR (400 MHz, DMSO) δ 14.50 (s, 1H), 12.39 (s, 1H), 8.90 (d, J = 3.0Hz, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 8.02 (m, 2H), 6.74-6.61 (m, 1H),5.17 (dd, J = 64.3, 3.1 Hz, 1H), 4.39 (m, 1H), 2.60 (s, 3H), 1.84-1.50(m, 2H). 424 98% 1-5 

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.22 (s, 1H), 12.42 (s, 1H),8.94 (s, 1H), 8.61 (d, J = 2.0 Hz. 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.20(d, J = 8.5 Hz, 1H), 8.03 (d, J = 9.6 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H),4.51-4.34 (m, 1H), 1.29-1.19 (m, 2H), 1.17-1.05 (m, 2H). 426 98% 1-7 

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 11.27 (s, 1H),8.91 (s, 1H), 8.04 (d, J = 9.5 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.78(s, 2H), 6.69 (d, J = 9.5 Hz, 1H), 4.49-4.30 (m, 1H), 2.65 (s, 3H), 1.25(d, J = 6.7 Hz, 2H), 1.08 (s, 2H). 439 98% 1-8 

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 11.99 (s, 1H),8.91 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.60(s, 1H), 7.57 (d, J = 11.5 Hz, 1H), 6.66 (d, J = 9.6 Hz, 1H), 4.51-4.29(m, 1H), 1.25 (d, J = 6.3 Hz, 2H), 1.15-0.94 (m, 2H). 423 98% 1-9 

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 11.30 (s, 1H),8.82 (s, 1H), 8.15-8.03 (m, 1H), 8.00-7.93 (d, J = 9.1 Hz, 1H),7.93-7.80 (d, J = 12.9 Hz, 2H), 6.79-6.51 (d, J = 9.4 Hz, 1H), 4.26-4.15(m, 1H), 3.51-3.38 (s, 3H), 1.31-1.09 (m, 4H). 455 93% 1-10

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69-14.59 (s, 1H),12.08-11.94 (s, 1H), 8.90-8.74 (s, 1H), 8.13-8.01 (d, J = 1.8 Hz, 1H),7.99-7.91 (d, J = 9.1 Hz, 1H), 7.77-7.71 (s, 1H), 7.68-7.59 (d, J = 11.6Hz, 1H), 6.71-6.62 (d, J = 9.6 Hz, 1H), 4.30-4.17 (ddd, J = 11.2, 7.5,4.7 Hz, 1H), 3.47-3.39 (s, 3H), 1.22-1.11 (m, 4H) 439 95% 1-11

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 9.92 (s, 1H),8.91 (s, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.81(s, 1H), 7.62-7.53 (m, 4H), 7.52-7.47 (m, 1H), 7.46 (s, 1H), 6.65 (d, J= 9.5 Hz, 1H), 4.65-4.23 (m, 1H), 2.70 (s, 3H), 1.24 (d, J = 7.0 Hz,2H), 1.07 (s, 2H). 481 98% 1-12

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 12.23 (s, 1H),8.92 (s, 1H), 8.10 (d, J = 9.5 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.87(s, 1H), 7.70 (s, 1H), 6.70 (d, J = 9.3 Hz, 1H), 4.43 (s, 1H), 2.64 (s,3H), 1.23 (s, 2H), 1.07 (d, J = 12.5 Hz, 2H). 489 98% 1-13

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.55 (s, 1H),8.91 (s, 1H), 8.04 (d, J = 9.5 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.84(s, 1H), 7.74 (s, 1H), 6.68 (d, J = 9.4 Hz, 1H), 4.75 (s, 1H), 4.40 (m,1H), 2.64 (s, 3H), 1.25 (d, J = 6.9 Hz, 2H), 1.08 (s, 2H). 429 90% 1-14

Me Cyclopropyl ¹H NMR (400 MHz. DMSO) δ 14.70 (s, 1H), 11.06 (s, 1H),8.91 (s, 1H), 8.05- 7.87 (m, 2H), 7.31 (s, 1H), 7.16 (s, 1H), 6.60 (d, J= 9.5 Hz, 1H), 4.40 (dd, J = 7.0, 3.4 Hz, 1H), 3.94 (s, 3H), 2 65 (s,3H), 1.25 (d, J = 7.1 Hz, 2H), 1.08 (s, 2H). 435 90% 1-15

Me Cyclopropyl ¹H NMR (400 MHz. DMSO) δ 14.65 (s, 1H), 10.97 (s, 1H),8.92 (s, 1H), 8.28-8.06 (m, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H),6.74 (d, J = 8.5 Hz, 1H), 4.49-4.33 (m, 1H), 2.64 (s, 3H), 1.25 (d, J =6.8 Hz, 2H), 1.10 (s, 2H). 473 90% 1-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.95 (s, 1H),8.91 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.76 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 9.5 Hz, 1H), 4.40 (s,1H), 2.63 (s, 3H), 1.25 (d, J = 6.1 Hz, 2H), 1.07 (s, 2H). 405 98% 1-17

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.76 (s, 1H),8.92 (s, 1H), 8.03 (d, J = 9.7 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.93(s, 1H), 7.83 (s, 1H), 6.68 (d, J = 9.4 Hz, 1H), 2.65 (s, 3H), 1.25 (m,2H), 1.07 (m, 2H). 482; 484 96% 1-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 11.86 (s, 1H),8.92 (s, 1H), 8.16 (m, 3H), 8.00 (d, J = 8.7 Hz, 1H), 6.80 (s, 1H), 4.42(s, 1H), 2.65 (s, 3H), 1.26 (m, 2H), 1.09 (m, 2H). 430 96% 1-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.10 (s, 1H),8.90 (s, 1H), 7.97 (t, J = 9.04 Hz, 2H), 7.58 (s, 1H), 7.39 (s, 1H),6.59 (d, J = 9.48 Hz, 1H), 4.39 (dt, J = 3.29, 6.75 Hz, 1H), 3.36 (s,3H), 2.63 (s, 3H), 1.25 (d, J = 6.45 Hz, 2H), 1.06 (s, 2H). 419 96% 1-20

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 8.93 (s, 1H),8.21 (s, 1H), 8.18 (s, 1H), 8.15 (d, J = 9.7 Hz, 1H), 8.02 (d, J = 8.9Hz, 1H), 6.81 (d, J = 9.7 Hz, 1H), 6.24 (s, 2H), 4.41 (m, 2H), 2.65 (s,4H), 1.25 (m, 2H), 1.10 (m, 2H). 461 90% 1-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 12.18 (s, 1H),8.91 (s, 1H), 8.14 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.7Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.28 (d, J= 7.4 Hz, 1H), 4.43 (s, 1H), 2.71 (s, 3H), 1.24 (s, 2H), 1.05 (s, 2H).405 98% 1-22

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.91 (s, 1H),8.16 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J = 7.3Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 6.7 Hz, 1H), 4.42 (s,1H), 3.74 (s, 3H), 2.69 (s, 3H), 1.23 (s, 2H), 1.05 (s, 2H). 419 95%1-23

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 12.04 (s, 1H),8.93 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.88 (t, J = 7.5 Hz, 1H), 7.48(d, J = 8.1 Hz, 1H), 7.35 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H),6.49 (d, J = 9.7 Hz, 1H), 4.39 (s, 1H), 2.50 (s, 3H), 1.16 (m, 4H). 40596% 1-24

Me Cyclopropyl ¹H NMR (400 MHz. DMSO) δ 14.82 (s, 1H), 10.88 (s, 1H),8.95 (s, 1H), 8.20-7.94 (m, 2H), 7.86 (d, J = 30.6 Hz, 1H), 7.44 (d, J =7.5 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 4.41 (s, 1H), 2.67 (s, 3H),1.47-0.92 (m, 4H) 405 90% 1-25

Me Cyclopropyl ¹H NMR (400 MHz. DMSO) δ 14.66 (s, 1H), 12.12 (s, 1H),8.94 (s, 1H), 6.06 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 7.0Hz, 1H), 7.13 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.40 (m,1H), 2.62 (s, 3H), 1.28-1.04 (m, 4H). 405 90% 1-26

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.88 (s, 1H),8.92 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 7.8 Hz, 1H), 7.29(s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 9.6 Hz, 1H), 4.40 (s,1H), 2.62 (s, 3H), 1.24 (d, J = 5.6 Hz, 2H), 1.07 (s, 2H). 405 94% 1-27

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 11.57 (s, 1H),11.48 (s, 1H), 8.97 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 760(d, J = 8.1 Hz, 1H), 7.49 (d, J = 6.2 Hz, 1H), 5.86 (s, 1H), 4.45 (s,1H), 2.68 (s, 3H), 1.30 (d, J = 6.7 Hz, 2H), 1.13 (s, 2H). 421 98% 1-28

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 10.73 (s, 1H),8.90 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.28(d, J = 7.6 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.24 (s, 2H), 1.06 (s,2H). 466 95% 1-29

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.96 (s, 1H),8.81 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.87(s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.57 (dd, J= 9.5, 1.7 Hz, 1H), 4.32-4.10 (m, 1H), 3.38 (s, 3H), 1.18 (m, 4H). 42198% 1-30

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.41 (s, 1H), 11.96 (s, 1H),8.91 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.95 (d, 9.1 Hz, 1H), 7.80 (s,1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.62 (dd, J =9.5, 1.7 Hz, 1H), 4.32-4.10 (m, 1H), 1.30 (m, 2H), 1.18 (m, 2H). 425 96%1-31

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.89 (s, 1H),8.82 (s, 1H), 8.17- 7.90 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.48 (s,1H), 7.35 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 11.2 Hz, 1H), 4.28-4.14 (m,1H), 3.41 (s, 4H), 1.18 (m, 4H). 421 90% 1-32

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.78 (s, 1H),8.91 (s, 1H), 7.98 (d, J = 8.77 Hz, 1H), 7.72 (s, 1H), 7.54 (s, 1H),7.50-7.44 (m, 1H), 6.48 (s, 1H), 2.63 (s, 3H), 2.44 (s, 3H), 1.28-1.21(m, 2H), 1.12-1.02 (m, 2H). 419 96% 1-33

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 13.15 (s, 1H),8.92 (s, 1H), 8.87 (s, 1H), 8.77 (d, J = 1.74 Hz, 1H), 8.38 (d, J = 1.97Hz, 1H), 8.02 (d, J = 8.86 Hz, 1H), 4.42 (tt, J = 3.74, 7.15 Hz, 1H),2.66 (s, 3H), 1.25 (q, J = 6.85 Hz, 2H), 1.08 (s, 2H). 431 96% 1-34

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.92 (s, 1H), 8.31(d, J = 8.86 Hz, 1H), 8.16 (d, J = 8.54 Hz, 1H), 8.03 (d, J = 8.91 Hz,1H), 6.51 (s, 1H), 4.44 (tt, J = 3.64, 7.02 Hz, 2H), 2.69 (s, 3H), 2.51(s, 3H), 1.24 (d, J = 6.83 Hz, 2H), 1.10 (s, 2H). 420 95% 1-35

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75-14.55 (m, 1H), 9.83-9.67(d, J = 3.2 Hz, 1H), 8.89-8.73 (s, 1H), 7.96-7.86 (d, J = 9.1 Hz, 1H),7.58-7.47 (s, 1H), 7.42-7.34 (s, 1H), 4.30-4.14 (tt, J = 7.3, 4.5 Hz,1H), 3.52-3.39 (s, 3H), 3.11-2.95 (t, J = 7.5 Hz, 2H), 2.62-2.56 (dd, J= 8.5, 6.3 Hz, 2H), 1.21-1.12 (m, 4H). 457 99% 1-36

OMe Cyclopropyl ¹H NMR (400 MHz, CDCl₃) δ 14.52-14.39 (s, 1H), 8.87-8.82(s, 1H), 8.01-7.92 (m, 1H), 7.75-7.69 (s, 1H), 7.39-7.34 (t, J = 1.7 Hz,1H), 7.21-7.18 (s, 1H), 6.79-6.69 (dd, J = 17.3, 11.0 Hz, 1H), 5.70-5.62(d, J = 17.3 Hz, 1H), 5.54-5.44 (d, J = 11.0 Hz, 1H), 4.09-3.99 (d, J =3.7 Hz, 1H), 3.45-3.36 (s, 3H), 3.03-2.95 (dd, J = 8.5, 6.5 Hz, 2H), 44985% 2.68-2.59 (dd, J = 8.7, 6.5 Hz, 2H), 1.26-1.21 (dd, J = 5.2, 1.8 Hz,2H), 1.11-1.03 (dt, J = 4.0, 1.9 Hz, 2H). 1-37

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73-14.60 (s, 1H),10.38-10.26 (s, 1H), 8.84-8.76 (s, 1H), 7.96-7.88 (d, J = 9.1 Hz, 1H),7.36-7.28 (d, J = 11.2 Hz, 1H), 7.25-7.19 (s, 1H), 4.29-4.18 (ddd, J =11.3, 7.3, 4.4 Hz, 1H), 3.47-3.43 (s, 3H), 3.07-2.98 (t, J = 7.4 Hz,2H), 2.60-2.53 (dd, J = 8.5, 6.5 Hz. 2H), 1.21-1.08 (d, J = 5.3 Hz, 4H).441 85% 1-38

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 9.62 (s, 1H),8.79 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H),4.39-4.16 (m, 1H), 3.42 (s, 3H), 3.03-2.88 (m, 2H), 2.54 (m, 5H), 1.16(m, 4H). 436 99% 1-39

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.13-14.27 (m, 1H),10.76-10.64 (s, 5H), 8.98-8.88 (s, 1H), 8.19-8.14 (d, J = 2.2 Hz, 1H),8.00-7.94 (d, J = 8.7 Hz, 1H), 7.75-7.70 (d, J = 2.1 Hz, 1H), 4.49-4.32(tt, J = 7.3, 3.8 Hz, 1H), 3.03-2.95 (m, 2H), 2.69-2.84 (s, 3H),2.62-2.56 (t, J = 7.5 Hz, 2H), 1.28-1.22 (m, 2H), 1.09-1.03 (m, 2H). 40890% 1-40

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 12.01 (s, 1H),8.92 (s, 1H), 8.53 (s, 1H), 8.08-7.98 (m, 2H), 7.72 (s, 1H), 6.85 (d, J= 9.75 Hz, 1H), 4.41 (s, 1H), 3.34 (s, 1H), 2.65 (s, 3H), 2.54 (s, 3H),1.24 (d, J = 6.54 Hz, 2H), 1.09 (s, 2H). 406 96% 1-41

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.51 (s, 1H), 9.00-8.91(m, 2H), 8.60-8.53 (s, 1H), 8.18-8.09 (t, J = 8.4 Hz, 2H), 8.09-8.02 (m,1H), 7.95-7.84 (s, 1H), 7.79-7.68 (s, 1H), 4.51-4.31 (s, 1H), 2.79-2.61(s, 3H), 1.36-1.20 (d, J = 6.9 Hz, 2H), 1.16-1.04 (s, 2H). 389 100% 1-42

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.88 (d, J = 2.6 Hz, 1H),8.95-8.82 (d, J = 2.5 Hz, 1H), 8.05-7.94 (d, J = 6.7 Hz, 1H), 7.89-7.77(d, J = 9.4 Hz, 1H), 7.62-7.40 (m, 3H), 6.33-6.21 (s, 1H), 5.59-5.49 (s,2H), 4.48- 4.35 (s, 1H), 2.86-2.76 (s, 3H), 1.30-1.15 392 100%  (d, J =7.0 Hz, 2H), 1.00-0.88 (s, 2H). 1-43

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.05-8.91 (s, 1H), 8.87-8.77 (s,1H), 8.43-8.36 (s, 1H), 8.14-8.06 (d, J = 7.3 Hz, 1H), 8.02-7.88 (d, J =21.7 Hz, 2H), 7.74-7.62 (d, J = 8.7 Hz, 1H), 7.59-7.51 (s, 1H),4.35-4.15 (s, 1H), 2.73-2.53 (m, 3H), 1.05 -0.93 (s, 2H), 389 97%0.85-0.71 (d, J = 8.0 Hz, 2H). 1-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72-14.59 (s, 1H), 9.01-8.91(s, 1H), 8.88-8.80 (s, 1H), 8.66-8.56 (d, J = 8.6 Hz, 1H), 8.25-8.16 (d,J = 8.0 Hz, 1H), 8.14-8.09 (s, 1H), 8.08-8.01 (d, J = 8.6 Hz, 1H),7.95-7.89 (d, J = 8.7 Hz, 1H), 7.88-7.79 (d, J = 7.7 Hz, 1H), 4.51-4.35(s, 1H), 2.75-2.67 (s, 3H), 1.30-1.19 (d, J = 6.8 Hz, 2H), 1.16-1.07 (s,2H). 405 97.5%   1-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.58 (s, 1H), 9.00-8.88(s, 1H), 8.19-8.07 (d, J = 8.3 Hz, 1H), 8.07-7.94 (m, 4H), 7.68-7.58 (d,J = 6.0 Hz, 2H), 7.57-7.48 (d, J = 8.2 Hz, 1H), 4.49-4.33 (s, 1H),2.72-2.59 (s, 3H), 1.33-1.19 (d, 388 98% J = 7.4 Hz, 2H), 1.16-1.00 (s,2H). 1-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.69-9.59 (s, 1H), 9.01-8.92 (d,J = 2.5 Hz, 1H), 8.69-8.58 (d, J = 2.4 Hz, 1H), 8.47-8.34 (d, J = 7.6Hz, 1H), 8.14-8.04 (d, J = 8.1 Hz, 1H), 7.95-7.80 (t, J = 8.7 Hz, 2H),7.57-7.46 (d, J = 7.9 Hz, 1H), 4.48-4.34 (s, 1H), 2.52-2.50 (s, 3H),1.29-1.01 (m, 4H). 389 98% 1-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.96-14.46 (s, 1H), 12.04-11.50(s, 1H), 8.98-8.89 (s, 1H), 8.34-8.17 (d, J = 12.3 Hz, 1H), 8.17-8.01(m, 2H), 7.97-7.90 (d, J = 8.1 Hz, 1H), 4.48-4.36 (dd, J = 7.3, 4.1 Hz,1H), 2.66-2.56 (s, 3H), 1.31-1.17 (d, J = 7.1 Hz, 2H), 1.15-1.03 (s,2H). 422 99% 1-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.19-9.11 (s, 1H), 8.98-8.92 (s,1H), 8.45-8.39 (s, 1H), 8.13-8.00 (dd, J = 16.7, 8.4 Hz, 2H), 7.80-7.69(t, J = 7.7 Hz, 1H), 7.66-7.55 (t, J = 7.7 Hz, 1H), 7.38-7.29 (d, J =8.3 Hz, 1H), 4.47-4.34 (s, 1H), 2.65-2.54 (s, 3H), 1.28-1.07 (m, 4H).405 98% 1-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69-14.45 (s, 1H), 10.31-10.19(s, 1H), 9.06-8.94 (d, J = 3.6 Hz, 2H), 8.73-8.62 (d, J = 8.2 Hz, 1H),8.61-8.43 (m, 2H), 8.32-8.21 (t, J = 7.5 Hz, 1H), 8.21-8.11 (m, 2H),7.83-7.71 (d, J = 8.3 Hz, 1H), 4.67-4.52 (s, 3H), 4.50-4.39 (d, J = 7.6Hz, 1H), 2.52-2.50 (m, 3H), 1.32-1.03 (m, 4H). 404 100%  1-50

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72-14.45 (s, 1H), 9.88-9.78(s, 1H), 9.58-9.48 (s, 1H), 9.02-8.92 (s, 1H), 8.70-8.60 (d, J = 9.0 Hz,1H), 8.59-8.51 (d, J = 8.2 Hz, 1H), 8.46-8.36 (t, J = 7.9 Hz, 1H),8.24-8.06 (t, J = 9.7 Hz, 2H), 4.78-4.67 (s, 2H), 4.53-4.40 (s, 1H),2.82-2.71 (s, 3H), 1.37-1.18 (d, J = 6.4 Hz, 2H), 1.16-1.07 (m, 2H). 40498% 1-51

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.10-9.01 (d, J = 4.0 Hz, 1H),8.98-8.91 (d, J = 2.6 Hz, 1H), 8.30-8.19 (d, J = 8.4 Hz, 1H), 8.14-8.07(s, 1H), 8.05-7.97 (t, J = 7.7 Hz, 1H), 7.96-7.89 (d, J = 8.4 Hz, 1H),7.78-7.68 (d, J = 6.8 Hz, 1H), 7.65 7.57 (m, 1H), 4.45-4.33 (s, 1H),2.48-2.40 (d, J = 2.8 Hz, 3H), 1.28-1.03 (m, 4H). 389 93.6%   1-52

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.78-14.66 (s, 1H), 9.06-8.97(s, 1H), 8.96-8.88 (s, 1H), 8.54-8.46 (d, J = 8.1 Hz, 1H), 8.26-8.14 (d,J = 8.3 Hz, 1H), 8.14-8.06 (s, 1H), 8.06-7.98 (d, J = 8.6 Hz, 1H),7.74-7.58 (d, J = 8.3 Hz, 2H), 4.51-4.29 (s, 1H), 2.73-2.60 (s, 3H), 389100%  1.29-1.18 (d, J = 7.0 Hz, 2H), 1.15-1.07 (s, 2H). 1-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.96-8.88 (d, J = 2.4 Hz, 1H),8.85-8.78 (s, 1H), 8.57-8.47 (d, J = 8.2 Hz, 1H), 8.25-8.13 (d, J = 8.3Hz, 1H), 8.03-7.95 (d, J = 8.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.69-7.54 (d,J = 8.7 Hz, 1H), 4.44-4.31 (s, 1H), 2.48-2.42 (s, 3H), 1.29-1.16 (d, J =7.6 Hz, 2H), 1.15-1.02 (s, 2H). 389 98% 1-54

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.17-9.09 (s, 1H), 9.01-8.91 (d,J = 2.7 Hz, 1H), 8.26-8.17 (d, J = 8.5 Hz, 1H), 8.15-8.06 (d, J = 8.5Hz, 1H), 7.94-7.84 (s, 1H), 2.48-2.42 (m, 2H), 7.72-7.59 (d, J = 9.2 Hz,2H), 7.56-7.45 (d, J = 8.3 Hz, 1H), 4.45- 4.35 (s, 1H), 2.52-2.45 (s,3H), 1.29-1.03 (dd, J = 16.6, 7.5 Hz, 4H). 389 98% 1-55

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.08-14.78 (s, 1H), 8.95-8.83(s, 2H), 8.48-8.37 (d, J = 6.0 Hz, 1H), 8.33-8.19 (d, J = 8.2 Hz, 1H),8.14-8.02 (d, J = 8.5 Hz, 1H), 7.94-7.76 (m, 2H), 7.68-7.59 (d, J = 7.1Hz, 1H), 7.58-7.49 (t, J = 7.2 Hz, 1H), 4.47-4.34 (s, 1H), 2.73-2.56 (s,3H), 1.31-0.99 (m, 4H). 405 95% 1-56

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.00-8.91 (s, 1H), 8.85-8.75 (d,J = 6.1 Hz, 1H), 8.73-8.64 (d, J = 8.6 Hz, 1H), 8.13-8.05 (d, J = 8.4Hz, 1H), 7.97-7.86 (d, J = 8.1 Hz, 1H), 7.80-7.71 (s, 1H), 7.65-7.58 (d,J = 5.8 Hz, 1H), 7.57-7.48 (d, J = 8.4 Hz, 1H), 4.46-4.35 (s, 1H),2.57-2.52 (s, 3H), 1.28-1.04 (m, 4H). 405 96% 1-57

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.95-14.35 (m, 1H), 9.01-8.90(t, J = 2.0 Hz, 1H), 8.80-8.63 (m, 2H), 8.13-8.06 (m, 1H), 8.04-7.95 (t,J = 7.8 Hz, 1H), 7.84-7.75 (d, J = 6.5 Hz, 1H), 7.52-7.41 (ddd, J =10.0, 5.1, 2.5 Hz, 1H), 7.38-7.29 (d, J = 8.4 Hz, 1H), 4.46-4.32 (d, J =6.9 Hz, 1H), 2.49-2.44 (s, 3H), 1.29-0.99 (m, 4H). 405 93.3%   1-58

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.98-8.89 (s, 1H), 8.73-8.64 (d,J = 6.6 Hz, 1H), 8.58-8.52 (s, 1H), 8.35-8.26 (d, J = 8.2 Hz, 1H),8.12-7.99 (t, J = 10.7 Hz, 2H), 7.83-7.75 (d, J = 8.3 Hz, 1H), 7.65-7.53(s, 1H), 4.46-4.36 (s, 1H), 2.65-2.59 (s, 3H), 1.29-1.19 405 96.2%   (d,J = 7.8 Hz, 2H), 1.14-1.07 (s, 2H). 1-59

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.96-8.87 (s, 1H), 8.75-8.64 (d,J = 7.2 Hz, 2H), 8.28-8.19 (s, 1H), 8.10-7.99 (d, J = 8.5 Hz, 2H),7.90-7.80 (d, J = 9.0 Hz, 1H), 7.63-7.52 (s, 1H), 4.48-4.34 (s, 1H),2.65-2.57 (s, 3H), 1.30-1.18 (d, J = 7.1 Hz, 2H), 1.14-1.02 (s, 2H). 40599% 1-60

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.77- 9.61 (s, 1H), 9.00-8.90(d, J = 3.1 Hz, 1H), 8.75-8.62 (d, J = 5.8 Hz, 1H), 8.57-8.42 (d, J =8.2 Hz, 1H), 8.31-8.21 (s, 1H), 8.22-8.13 (d, J = 5.3 Hz, 1H), 8.11-8.01(d, J = 8.7 Hz, 1H), 7.94-7.81 (d, J = 8.4 Hz, 1H), 4.49-4.34 (s, 1H),2.68-2.59 369 93.6%   (s, 3H), 1.34-1.18 (d, J = 7.6 Hz, 2H), 1.15-1.00(s, 2H). 1-61

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.19-9.10 (s, 1H), 9.03-8.95 (s,1H), 8.37-8.27 (d, J = 6.9 Hz, 1H), 8.18-8.05 (m, 4H), 7.81-7.73 (d, J =8.4 Hz, 1H), 4.52-4.42 (t, J = 5.2 Hz, 1H), 2.74-2.65 (s, 3H), 1.36-1.27(d, J = 7.1 Hz, 2H), 1.19-1.10 (s, 2H). 405 1005 1-62

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82-14.70 (s, 1H), 11.54-11.41(s, 1H), 9.03-8.93 (s, 1H), 8.44-8.33 (d, J = 8.2 Hz, 1H), 8.14-8.01 (d,J = 8.0 Hz, 1H), 7.84-7.75 (s, 1H), 7.58-7.51 (d, J = 7.6 Hz, 1H),7.39-7.26 (s, 1H), 6.76-6.64 (d, J = 6.6 Hz, 1H), 4.52-4.40 (s, 1H),2.70-2.61 (s, 3H), 1.37-1.22 (d, J = 6.8 Hz, 2H), 1.19-1.04 (s, 2H). 405100%  1-63

¹H NMR (400 MHz, DMSO) δ 15.18 (s, 1H), 12.31 (s, 1H), 9.09 (s, 1H),8.82 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.03 (t, J = 9.3 Hz,2H), 7.76 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 5.00 (d, J =6.7 Hz, 1H), 4.58 (d, J = 10.8 Hz, 1H), 4.45 (d, J = 10.0 Hz, 1H), 2.54(s, 1H), 1.52 (d, J = 6.7 Hz, 3H). 390 98% 1-64

¹H NMR (400 MHz, DMSO) δ 14.96 (s, 1H), 12.35 (s, 1H), 9.10 (s, 1H),8.68 (s, 1H), 8.34 (s, 1H), 8.01 (d, J = 9.53 Hz, 1H), 7.79 (d, J = 9.70Hz, 1H), 6.64 (d, J = 9.45 Hz, 1H), 5.01 (d, J = 6.68 Hz, 1H), 4.60-4.54(m, 1H), 4.46 (d, J = 9.78 Hz, 1H), 1.49 (d, J = 6.71 Hz, 3H). 408 96%1-65

¹H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.95 (s, 1H), 8.87 (d, J = 15.4Hz, 1H), 8.41-8.22 (m, 3H), 8.01 (t, J = 7.3 Hz, 1H), 7.85 (t, J = 7.3Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 4.45 (m, 1H), 2.77 (s, 3H), 1.31 (d,J = 6.2 Hz, 2H), 1.11 (s, 2H). 371 97%

TABLE 2

Com- pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 2-1

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 7.98 (s, 1H), 7.80(s, 1H), 7.33 (d, J = 8.90 Hz, 1H), 7.16 (d, J = 9.30 Hz, 1H), 3.66 (d,J = 3.58 Hz, 1H), 1.96 (s, 3H), 0.58 (d, J = 5.78. Hz, 1H), 0.37 (d, J =1.61, Hz, 2H). 357 94% 2-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.48 (d, J = 2.77Hz, 1H), 8.13 (s, 1H), 8.01 (d, J = 8.72 Hz, 1H), 7.61 (s, 1H),4.50-4.30 (m, 1H), 3.49 (d, J = 5.30 Hz, 5H), 3.38-3.29 (m, 5H), 2.66(d, J = 15.95 Hz, 3H), 1.43 (s, 9H), 1.28-1.21 (m, 2H), 1.08 (s, 2H).523 98% 2-3

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.79 (d, J = 5.61Hz, 2H), 8.01 (d, J = 8.93 Hz, 1H), 7.50 (d, J = 5.50 Hz, 2H), 4.40 (s,1H), 2.61 (s, 3H), 1.24 (d, J = 5.97 Hz, 2H), 1.07 (s, 2H). 339 98% 2-4

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.00 (s, 2H), 8.92 (s, 1H), 8.49(d, J = 2.73 Hz, 1H), 8.12 (s, 1H), 7.98 (t, J = 11.57 Hz, 1H), 7.56 (s,1H), 4.44-4.34 (m, 1H), 3.64 (s, 5H), 3.26 (s, 4H), 2.62 (s, 3H), 1.23(d, J = 6.27 Hz, 2H), 1.07 (s, 2H). 423 95% 2-5

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.71 (t, J = 26.47Hz, 1H), 8.04 (d, J = 8.68 Hz, 2H), 7.61 (d, J= 45.28 Hz, 1H), 4.44-4.38(m, 1H), 2.55 (s, 2H), 2.34 (d, J = 9.33 Hz, 3H), 1.23 (s, 2H) 1.06 (dd,J = 4.45, 8.57 Hz, 2H). 353 95% 2-6

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.92 (s, 1H),8.83 (t, J = 8.69 Hz, 1H), 8.65 (dt, J = 8.70, 17.42 Hz, 1H), 8.05 (d, J= 8.87 Hz, 1H), 7.73-7.52 (m, 1H), 4.41 (tt J = 3.77, 7.16 Hz, 1H), 2.64(s, 3H), 1.31-1.16 (m, 2H), 1.10-0.97 (m, 2H). 357 98% 2-7

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.85-8.61 (m, 2H),8.03 (d, J = 6.60 Hz, 1H), 7.96 (s, 2H), 7.69 (dd, J = 5.19, 7.64 Hz,1H), 4.41 (ddd, J = 3.87, 7.26, 10.97 Hz, 2H), 2.75-2.72 (m, 5H),1.33-1.20 (m, 3H), 1.13-1.03 (m, 2H). 339 98% 2-8

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.92-7.71 (m, 2H),7.55 (t, J = 17.62 Hz, 1H), 6.84 (t, J = 36.31 Hz, 1H), 4.16-4.04 (m,1H), 3.02 (s, 5H), 1.09-1.01 (m, 2H), 0.81 (q, J = 7.23 Hz, 2H). 355 98%2-9

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 8.06 (t, J = 38.62 Hz, 2H), 7.68(dd, J = 8.35, 33.76 Hz, 2H), 7.47 (d, J = 8.87 Hz, 1H), 7.13-6.77 (m,2H), 4.33 (s, 1H), 3.97 (d, J = 7.85 Hz, 3H), 2.20-1.90 (m, 2H),1.35-1.22 (m, 1H), 1.05 (s, 1H). 369 98% 2-10

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.06 (s, 1H), 8.33 (s, 1H), 8.01(d, J = 9.18 Hz, 1H), 7.67 (t, J = 24.14 Hz, 2H), 7.17 (s, 1H), 4.37 (s,1H), 3.94 (s, 3H), 2.66 (s, 3H), 1.32 (d, J = 6.60 Hz, 2H), 1.07 (s,2H). 369 98% 2-11

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.05 (s, 1H), 8.29 (s, 2H), 8.09(d, J = 7.83 Hz, 1H), 7.94 (d, J = 23.80 Hz, 2H), 7.39-7.20 (m, 2H),7.09 (s, 1H), 4.36 (s, 1H), 2.77 (s, 3H), 1.30 (s, 2H), 1.09 (s, 2H).466 98% 2-12

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.02 (s, 1H), 8.40 (d, J = 92.33Hz, 2H), 8.16-8.03 (m, 2H), 7.98-7.80 (m, 1H), 7.75-7.50 (m, 2H), 4.34(s, 1H), 3.82 (d, J = 24.28 Hz, 4H), 3.45 (s, 4H), 2.70 (d, J = 23.16Hz, 3H), 1.27 (dd, J = 11.61, 24.61 Hz, 3H), 1.09 (s, 2H). 424 98% 2-13

Me Cyclopropyl ¹H NMR(400 MHz, DMSO) δ 14.68 (s, 1H), 8.91 (s, 1H), 8.69(s, 1H), 7.97 (d, J = 8.46 Hz, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 4.40 (s,1H), 3.82 (d, J = 6.95 Hz, 2H), 3.21 (s, 2H), 2.63 (d, J = 43.98 Hz,3H), 1.22 (d, J = 5.36 Hz, 2H), 1.05 (s, 2H). 380 97% 2-14

Me Cyclopropyl ¹H HMR (400 MHz, DMSO) δ 14.69 (s, 2H), 8.91 (s, 1H),8.49 (s, 2H), 8.24 (s, 2H), 7.98 (d, J = 8.62 Hz, 1H), 4.41 (s, 1H),2.65 (d, J = 31.48 Hz, 3H), 1.24 (d, J = 6.48 Hz, 2H), 1.07 (s, 2H). 39999% 2-15

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.91 (s, 1H),8.13 (d, J = 25.11 Hz, 1H), 8.07 (s, 1H), 7.95 (dd, J = 8.95, 25.35 Hz,2H), 7.06 (d, J = 8.71 Hz, 1H), 4.41 (s, 1H), 2.65 (d, J = 25.72 Hz,3H), 1.22 (d, J = 5.45 Hz, 2H), 1.05 (s, 2H). 354 99% 2-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.74 (s, 1H), 8.54(t, J = 24.30 Hz, 2H), 7.99 (d, J = 8.68 Hz, 1H), 4.41 (s, 1H), 3.10 (d,J = 17.91 Hz, 3H), 2.70 (s, 3H), 1.25 (d, J = 5.66 Hz, 2H), 1.07 (s,2H). 413 99% 2-17

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 9.79 (s, 2H),8.92 (s, 1H), 8.61 (s, 1H), 8.01 (d, J = 13.11 Hz, 2H), 4.67 (d, J =32.94 Hz, 4H), 4.40 (s, 1H), 2.62 (s, 3H), 1.23 (s, 3H), 1.07 (s, 2H).380 97% 2-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.89 (s, 1H),8.27 (s, 1H), 8.07 (t, J = 6.62 Hz, 1H), 7.94 (d, J = 8.87 Hz, 1H), 7.28(s, 2H), 4.40 (tt, J = 3.75, 7.16 Hz, 1H), 3.31 (s, 1H), 2.67 (s, 3H),1.31-1.19 (m, 2H), 1.10-1.00 (m, 2H). 379 99% 2-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.93 (s, 1H), 8.70(s, 1H), 8.36 (s, 1H), 8.03 (d, J = 8.65 Hz, 1H), 4.41 (s, 2H), 2.65 (s,3H), 2.44 (s, 3H), 1.25 (d, J = 6.79 Hz, 2H), 1.10 (s, 2H). 420 97% 2-20

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.19 (d, J = 11.25Hz, 3H), 7.99 (d, J = 8.83 Hz, 1H), 7.62 (s, 1H), 4.41 (s, 2H), 2.69 (s,3H), 1.25 (d, J = 5.80 Hz, 2H), 1.05 (s, 2H). 397 99% 2-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.89 (s, 1H),8.11-7.87 (m, 2H), 7.74 (s, 1H), 6.71 (s, 2H), 4.39 (s, 1H), 2.63 (d, J= 29.40 Hz, 3H), 1.20 (t, J = 25.86 Hz, 2H), 0.99 (d, J = 41.43 Hz, 2H).388 98% 2-22

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.90 (s, 1H),8.26 (s, 1H), 7.95 (d, J = 8.81 Hz, 1H), 7.86 (s, 1H), 6.89 (s, 2H),4.39 (s, 1H), 2.66 (s, 3H), 1.24 (d, J = 5.61 Hz, 2H), 1.06 (s, 2H). 42298% 2-23

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.98 (s, 1H),8.13-8.02 (m, 2H), 7.92 (d, J = 14.79 Hz, 3H), 4.47 (s, 1H), 2.71 (d, J= 23.60 Hz, 3H), 2.31 (s, 3H), 1.29 (d, J = 5.54 Hz, 2H), 1.15 (d, J =22.69 Hz, 2H). 366 99% 2-24

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.79 (s, 1H),8.11 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 6.73 (s, 2H), 4.22 (s, 1H),3.46 (s, 3H), 3.31 (s, 2H), 1.16 (s, 4H). 404 98% 2-25

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.80 (s, 1H),8.39 (s, 1H), 8.13-7.81 (m, 2H), 6.91 (s, 2H), 4.23 (s, 1H), 3.31 (s,3H), 1.17 (d, J = 6.99 Hz, 3H). 436 99% 2-26

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (d, J = 61.68 Hz, 1H),8.76 (d, J = 28.90 Hz, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.92 (d, J =9.13 Hz, 1H), 4.23 (s, 1H), 3.46 (s, 3H), 1.17 (d, J = 7.13 Hz, 4H). 39596% 2-27

Me Cyclopropyl ¹H NMR (400 MHz, DMSO), 8.89 (s, 1H), 7.95-7.93 (m, 2H),7.83 (s, 1H), 7.60-6.57 (d, 1H), 4.39 (s, 1H), 2.63 (d, J = 29.40 Hz,3H), 1.20 (t, J = 25.86 Hz, 2H), 0.99 (d, J = 41.43 Hz, 2H). 372 98%2-28

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.94-8.66 (m,1H), 8.49-8.39 (m, 1H), 8.26 (d, J = 1.30 Hz, 1H), 7.91 (dd, J = 19.79,31.75 Hz, 2H), 4.27-4.17 (m, 1H), 3.50-3.42 (m, 3H), 1.17 (dt, J = 7.59,17.65 Hz, 3H). 398 98% 2-29

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.92 (d, J = 13.25Hz, 1H), 8.32 (d, J = 1.05 Hz, 1H), 8.17 (d, J = 1.69 Hz, 1H), 8.00 (t,J = 18.18 Hz, 1H), 7.83 (d, J = 33.09 Hz, 1H), 4.40 (dt, J = 3.59, 10.71Hz, 1H), 2.68 (d, J = 12.78 Hz, 3H), 1.25 (q, J = 6.89 Hz, 2H), 382 98%1.14-0.93 (m, 2H). 2-30

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 2H), 8.90 (s, 1H),7.97 (d, J = 8.81 Hz, 1H), 7.64 (d, J = 1.21 Hz, 1H), 7.34 (s, 1H), 4.40(td, J = 3.75, 7.19 Hz, 1H), 3.90 (s, 3H), 2.78-2.61 (m, 3H), 1.23 (q, J= 7.19 Hz, 2H), 1.16-0.97 (m, 2H). 384 95% 2-31

Me

¹H NMR (400 MHz, DMSO) δ 14.64 (s, 2H), 8.90 (s, 1H), 7.97 (d, J = 8.81Hz, 1H), 7.64 (d, J = 1.21 Hz, 1H), 7.34 (s, 1H), 4.40 (td, J = 3.75,7.19 Hz, 1H), 3.90 (s, 3H), 2.78-2.61 (m, 3H), 1.23 (q, J = 7.19 Hz,2H), 1.16-0.97 (m, 2H). 406 99% 2-32

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.90 (s, 1H),7.99 (d, J = 1.60 Hz, 1H), 7.95 (t, J = 10.20 Hz, 1H), 7.70-7.53 (m,1H), 4.39 (td, J = 3.61, 7.03 Hz, 1H), 2.62 (d, J = 19.25 Hz, 3H), 1.84(ddd, J = 5.42, 8.33, 13.56 Hz, 1H), 1.21 (t, J = 6.56 Hz, 1H), 1.05 (d,J = 8.64 Hz, 1H), 1.03-0.96 (m, 2H), 394 98% 0.78-0.65 (m, 2H). 2-33

Me

¹H NMR (400 MHz, DMSO) δ 8.88 (d, J = 3.01 Hz, 1H), 8.18 (s, 1H), 8.13(s, 1H), 8.09 (s, 1H), 7.99 (d, J = 8.77 Hz, 1H), 7.54 (s, 1H),5.29-5.01 (m, 1H), 4.50-4.31 (m, 1H), 2.71-2.57 (m, 2H), 1.76 (ddd, J =9.04, 15.14, 17.62 Hz, 1H), 1.53 (d, J = 26.94 Hz, 1H). 415 98% 2-34

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.11 (d, J = 8.56Hz, 1H), 8.02 (d, J = 0.96 Hz, 1H), 7.81 (d, J = 1.67 Hz, 1H), 4.44-4.39(m, 2H), 1.32- 1.17 (m, 2H), 1.17-1.04 (m, 2H). 408 94% 2-35

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.99 (s, 1H),7.92 (d, J = 9.3 Hz, 1H), 7.69 (d, J = 12.0 Hz, 1H), 4.29-4.14 (m, 1H),3.47 (s, 3H), 1.24-1.04 (m, 4H). 387 99% 2-36

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.92 (s, 1H),8.37 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.11-7.88 (m, 3H), 7.51 (s, 1H),4.55-4.30 (m, 3H), 3.20 (m, 2H), 2.68 (s, 3H), 1.25 (d, J = 6.4 Hz, 2H),1.08 (d, J = 7.0 Hz, 2H). 441 98% 2-37

OMe

¹H NMR (400 MHz, DMSO) δ 14.52 (s, 1H), 8.82 (d, J = 1.51 Hz, 1H), 8.38(s, 1H), 8.11 (s, 1H), 7.94 (d, J = 9.20 Hz, 1H), 7.36 (s, 2H), 5.10(ddd, J = 5.42, 8.45, 64.07 Hz, 1H), 4.24 -4.12 (m, 1H), 1.86-1.55 (m,2H). 413 98% 2-38

OMe

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.82 (d, J = 1.46 Hz, 1H), 8.15(d, J = 36.97 Hz, 1H), 7.92 (d, J = 9.24 Hz, 1H), 7.80 (s, 1H), 6.75 (s,2H), 5.10 (ddd, J = 5.43, 8.45, 64.08 Hz, 1H), 4.29-4.12 (m, 1H),1.93-1.53 (m, 2H). 422 98% 2-39

Me

¹H NMR (400 MHz, DMSO) δ 14.39 (s, 1H), 8.80 (s, 1H), 8.16-8.08 (m, 2H),7.98-7.86 (m, 2H), 7.69-7.59 (m, 1H), 7.37 (dd, J = 5.20, 11.82 Hz, 1H),7.26 (s, 2H), 1.67 (s, 3H). 451 99% 2-40

Me Cyclopropyl ¹H NMR (400 MHz, CDCl₃) δ 14.60-14.29 (s, 1H), 8.96-8.89(s, 1H), 8.05-7.96 (m, 2H), 7.48-7.40 (m, 4H), 7.40-7.33 (dt, J = 8.5,2.8 Hz, 1H), 7.33-7.29 (s, 1H), 4.88-4.75 (s, 2H), 4.17-3.98 (s, 1H),2.73-2.62 (s, 3H), 1.28-1.20 (m, 2H), 1.02-0.93 (s, 2H). 430 99% 2-41

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.68 (s, 1H), 8.99-8.81(s, 1H), 7.96-7.89 (d, J = 8.9 Hz, 1H), 7.88-7.81 (s, 1H), 7.36-7.20 (s,1H), 6.19-6.08 (s, 2H), 4.47-4.31 (s, 1H), 2.75-2.60 (s, 3H), 1.36-1.10(m, 6H), 1.10-0.94 (t, J = 3.1 Hz, 2H). 382 93% 2-42

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.67 (s, 3H), 8.97-8.85(s, 3H), 8.00-7.85 (m, 6H), 7.72-7.60 (t, J = 1.7 Hz, 3H), 6.97-6.81(dd, J = 17.3, 11.0 Hz, 3H), 6.45-6.27 (s, 6H), 5.85-5.70 (m, 4H),5.44-5.26 (dd, J = 11.0, 1.2 Hz, 3H), 4.47-4.33 (s, 1H), 2.76-2.60 38099% (s, 9H), 1.30-1.18 (m, 6H), 1.12-0.98 (m, 5H), 1.32 -1.20 (m, 7H).2-43

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95-8.90 (s, 1H), 8.36-8.31 (m,1H), 8.13-8.07 (d, J = 2.0 Hz, 1H), 8.02-7.97 (d, J = 8.8 Hz, 1H),4.49-4.36 (m, 3H), 2.90-2.79 (s, 5H), 2.76-2.67 (s, 3H), 1.33-1.20 (q, J= 6.9 Hz, 2H), 1.10-0.98 (m, 2H). 397 98% 2-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93-8.91 (s, 1H), 8.24-8.20 (m,1H), 8.01-7.96 (d, J = 8.8 Hz, 1H), 7.93-7.67 (t, J = 2.8 Hz, 1H),4.49-4.38 (tt, J = 7.2, 3.9 Hz, 1H), 4.24-4.14 (t, J = 5.5 Hz, 2H),2.85-2.77 (s, 6H), 1.29 -1.20 (m, 2H), 1,09-0.98 (m, 2H). 411 97% 2-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.94-8.89 (s, 1H), 8.15-8.09 (d,J = 2.1 Hz, 1H), 8.02-7.96 (d, J = 8.9 Hz, 1H), 7.92-7.88 (s, 1H),4.46-4.37 (m, 1H), 4.57-4.46 (s, 2H), 2.71-2.65 (s, 3H), 1.25-1.18 (d, J= 6.7 Hz, 2H), 1.10-0.98 (m, 2H). 384 90% 2-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.89 (s, 1H),8.35 (s, 2H), 7.94 (d, J = 8.67 Hz, 1H), 7.09 (s, 2H), 4.39 (s, 1H),2.70 (s, 3H), 1.24 (d, J = 5.31 Hz, 2H), 1.03 (s, 2H). 354 99% 2-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.89 (s, 1H),8.41 (s, 2H) 7.95 (d, J = 8.41 Hz, 1H), 7.60 (d, J = 28.12 Hz, 1H), 4.40(s, 1H), 2.88 (s, 3H), 2.70 (s, 3H), 1.25 (d, J = 5.56 Hz, 2H), 1.03 (s,2H). 369 99% 2-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.89 (s, 1H),8.39 (s, 2H), 7.95 (d, J = 8.73 Hz, 1H), 7.64 (s, 1H), 4.39 (s, 1H),2.70 (s, 3H), 2.53 (d, J = 9.32 Hz, 3H), 1.24 (d, J = 6.11 Hz, 2H), 1.17(t, J = 6.98 Hz, 2H), 1.03 (s, 2H). 383 97% 2-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 2H), 8.90 (s, 1H),8.48 (s, 2H), 7.96 (d, J = 8.59 Hz, 1H), 4.39 (s, 1H), 3.24 (d, J =22.01 Hz, 6H), 2.70 (s, 3H), 1.25 (d, J = 6.03 Hz, 2H), 1.04 (d, J =7.73 Hz, 2H). 383 98% 2-50

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.35 (s, 2H), 8.13(d, J = 8.6 Hz, 1H), 7.15 (s, 2H), 4.41 (m, 3.8 Hz, 1H), 1.37-1.17 (m,2H), 1.18-1.02 (m, 2H). 375 99% 2-51

Me

¹H NMR (400 MHz, DMSO) δ 8.87 (d, J = 3.2 Hz, 1H), 8.35 (d, J = 1.0 Hz,2H), 7.97 (d, J = 8.9 Hz, 1H), 7.08 (s, 2H), 5.33-4.97 (m, 2H), 4.37 (m,1H), 2.65 (s, 3H), 1.89-1.41 (m, 2H). 373 99% 2-52

MeO

¹H NMR (400 MHz, DMSO) δ 14.54 (s, 1H), 8.82 (d, J = 1.2 Hz, 1H), 8.44(s, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.10 (s, 2H), 5.09 (m, 1H), 4.37-3.96(m, 1H), 3.50 (s, 3H), 1.98-1.52 (m, 2H). 389 98% 2-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.91 (d, J = 4.9Hz, 1H), 8.76 (s, 2H), 8.15-7.85 (m, 1H), 4.63-4.29 (m, 1H), 2.50 (s,3H), 1.29-1.15 (m, 2H), 1.06 (d, J = 7.0 Hz, 2H). 384 99% 2-54

MeO Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.52 (s, 2H),8.00 (d, J = 9.2 Hz, 1H), 7.18 (s, 2H), 4.29 (m, 1H), 3.55 (s, 3H),1.27-1.11 (m, 4H). 371 99% 2-55

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.79 (s, 1H),8.19 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.81 (s, 1H), 6.91 (t, J = 5.6Hz, 1H), 4.29-4.11 (m, 1H), 3.53-3.41 (m, 5H), 1.26-1.06 (m, 7H). 43298% 2-56

¹H NMR (400 MHz, DMSO) ⁺δ 9.06 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 1.75Hz, 1H), 7.72 (d, J = 9.80 Hz, 1H), 7.29 (s, 2H), 5.06-4.90 (m, 1H),4.58 (d, J = 10.62 Hz, 1H), 4.44 (d, J = 9.71 Hz, 1H), 1.48 (d, J = 6.75Hz, 3H). 381 95% 2-57

¹HNMR (400 MHz, DMSO) δ 14.95 (s, 1H), 8.91 (s, 1H), 8.37-8.33 (d, J =2.5 Hz, 1H), 8.24-8.19 (d, J = 8.3 Hz, 1H), 8.14-8.10 (d, J = 2.5 Hz,1H), 7.58-7.51 (d, J = 8.3 Hz, 1H), 7.22 (s, 2H), 4.42-4.36 (tt, 7.1,3.7 Hz, 1H), 2.71 (s, 3H), 1.30-1.25 (m, 2H), 1.05-0.94 (m, 2H). 361 95%2-58

¹H NMR (400 MHz, DMSO) δ 14.95 (s, 1H), 8.89 (s, 1H), 8.32 (d, J = 3.5Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.53 (d,J = 8.2 Hz, 1H), 6.61 (s, 2H), 4.39 (s, 1H), 2.72 (s, 3H), 1.27 (d, J =6.1 Hz, 2H), 1.03 (s, 2H). 370 99% 2-59

¹H NMR (400 MHz, DMSO) δ 15.00 (s, 1H), 9.06 (s, 1H), 8.17 (s, 1H), 7.80(s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 6.86 (t, J = 5.7 Hz, 1H), 4.98 (d, J= 6.7 Hz, 1H), 4.57 (d, J = 10.2 Hz, 1H), 4.48-4.32 (m, 1H), 3.55-3.37(m, 2H), 1.48 (d, J = 6.8 Hz, 2H), 1.17 (t, J = 7.1 Hz, 2H). 418 98%2-60

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.18(s, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.80 (s, 1H), 6.92 (t J = 5.7 Hz,1H), 5.10 (ddd, J = 64.1, 8.4, 5.4 Hz, 1H), 4.32-4.06 (m, 1H), 3.58-3.37(m, 5H), 1.93-1.51 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). 450 98%

TABLE 3

Com- pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 3-1

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 9.08 (s, 1H),8.94 (s, 1H), 8.33 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H) 8.06(t, J = 8.5 Hz, 2H), 7.85 (d, J = 9.4 Hz, 1H), 4.49-4.38 (m, 1H), 2.70(s, 3H), 1.25 (d, J = 6.6 Hz, 2H), 1.09 (s, 2H). 378 98% 3-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83 (s, 1H), 9.38 (s, 1H),8.91 (d, J = 25.3 Hz, 1H), 8.79 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 8.8Hz, 1H), 8.01 (s, 1H), 4.44 (s, 1H), 2.75 (s, 3H), 1.25 (s, 2H), 1.09(s, 2H). 379 95% 3-3

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 9.41 (s, 1H),9.00 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 3.17 (s, 1H), 8.07 (s, 2H),7.86 (s, 1H), 7.61 (s, 1H), 4.49 (s, 1H), 2.79 (s, 3H), 1.31 (s, 3H),1.17 (s, 2H). 456 98% 3-4

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.57 (d, J = 5.1 Hz, 1H), 9.05(d, J = 6.5 Hz, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.11 (s,1H), 8.05 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 4.43 (s, 1H),2.68 (s, 3H), 1.24 (d, J = 5.0 Hz, 2H), 1.11 (s, 2H). 378 97% 3-5

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 9.13 (d, J = 6.3Hz, 1H), 8.90 (s, 1H), 8.53 (s, 1H), 8.31 (d, J = 11.7 Hz, 2H), 8.09 (d,J = 9.1 Hz, 1H), 7.72 (d, J = 6.8 Hz, 1H), 4.30 (s, 1H), 3.57 (s, 3H),1.25 (s, 4H). 394 95% 3-6

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.93 (s, 1H), 8.64(s, 1H), 8.04 (t, J = 9.2 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 4.42 (s,1H), 2.69 (s, 3H), 1.24 (s, 2H), 1.09 (s, 2H). 379 97% 3-7

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H, 9.33 (s, 1H),8.83 (s, 1H), 8.64 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 9.1Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 4.24 (s, 1H), 3.48 (s, 3H), 1.19 (d,J = 5.2 Hz, 4H). 395 98% 3-8

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 9.11 (s, 1H),8.93 (s, 1H), 8.22 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J = 8.9Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 4.43 (tt, J = 7.1, 3.7 Hz, 1H), 2.70(s, 3H), 1.26 (d, J = 6.8 Hz, 2H), 1.09 (s, 2H). 379 98% 3-9

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 9.07 (s, 1H),8.93 (s, 1H), 8.22 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.81 (s, 1H), 7.80(s, 1H), 4.49-4.37 (m, 1H), 2.70 (d, J = 21.5 Hz, 3H), 1.27 (t, J = 9.8Hz, 2H), 1.14-1.05 (m, 2H). 446 97% 3-10

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.94 (s, 2H),8.35 (s, 1H), 8.23 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.75 (s, 1H), 4.43(s, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 392 98%3-11

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H) 8.92 (s, 1H), 8.79(d, J = 1.2 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H),7.76 (d, J = 1.1 Hz, 1H), 7.58 (s, 1H), 4.42 (tt, J = 7.2, 3.8 Hz, 1H),2.70 (d, J = 20.2 Hz, 3H), 1.26 (d, J = 6.9 Hz, 2H), 1.15-1.03 (m, 2H).412 99% 3-12

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 8.94 (s, 1H), 8.88(s, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.89 (d, J= 9.3 Hz, 1H), 4.43 (s, 1H), 2.69 (s, 3H), 1.24 (d, J = 6.1 Hz, 2H),1.12 (s, 2H). 423 96% 3-13

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 8.90 (s, 1H),8.83 (s, 1H), 6.22 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.75(d, J = 1.0 Hz, 1H), 7.66 (s, 1H), 4.29-4.18 (m, 1H), 3.51 (d, J = 13.2Hz, 3H), 1.25-1.14 (m, 4H). 428 100% 3-14

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 9.19 (s, 1H),8.83 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.92 (s, 1H), 7.81(s, 1H), 4.25 (dt, J = 11.0, 5.7 Hz, 1H), 3.50 (d, J = 12.8 Hz, 3H),1.19 (m, 4H). 462 98% 3-15

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.93 (s, 1H), 8.51(s, 1H), 8.13 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 9.2 Hz,1H), 7.62 (d, J = 9.2 Hz, 1H), 7.55 (s,1H), 4.42 (s, 1H), 2.69 (s, 3H),1.24 (s, 2H) 1.10 (s, 2H). 421 98% 3-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.87-13.95 (m, 2H), 9.60 (s,1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.05 (t, J = 9.5 Hz, 2H), 7.71 (d, J =9.4 Hz, 1H), 4.46- 4.39 (m, 1H), 2.71 (m, 3H), 2.46 (s, 3H), 1.25 (d, J= 6.3 Hz, 2H), 1.11 (s, 2H). 459 98% 3-17

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.44-13.91 (m, 1H), 9.16 (s,1H), 8.95 (s, 1H), 8.37 (s, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.08 (s, 1H),7.81 (s, 1H), 4.43 (m, 1H), 1.23 (m, 2H), 1.16 (s, 2H). 398 98% 3-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.92 (s, 1H),8.68 (s, 1H), 8.19 (d, J = 2.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.73(d, J = 1.0 Hz, 1H), 7.32 (d, J = 11.7 Hz, 1H), 4.42 (m, 1H), 2.72 (s,3H), 1.25 (d, 2H), 1.12-1.04 (m, 2H). 396 98% 3-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.94 (s, 1H), 8.54(s, 1H), 8.36 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 8.00 (s, 1H), 4.49-4.38(m, 1H), 2.74 (s, 3H), 1.25 (d, J = 6.9 Hz, 2H), 1.11 (s, 2H). 423 98%3-20

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.88 (t, J = 4.2Hz, 1H), 8.22 (t, J = 2.4 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.82 (s,1H), 7.68 (s, 1H), 4.48- 4.36 (m, 1H), 1.26-1.19 (m, 2H), 1.14 (m, 2H).432 98% 3-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 9.32 (d, J = 1.2Hz, 1H), 8.93 (s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 8.02 (d, J = 8.8 Hz,1H), 4.43 (tt, J = 7.0, 3.6 Hz, 1H), 2.70 (d, J = 17.8 Hz, 3H),1.30-1.20 (m, 2H), 1.15-1.05 (m, 2H). 413 98% 3-22

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 9.22 (s, 1H),8.93 (s, 1H), 8.71 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 10.8Hz, 1H), 4.47-4.37 (m, 1H), 2.72 (s, 3H), 1.29-1.22 (m, 2H), 1.10 (s,2H). 397 99% 3-23

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 9.26 (s, 1H),8.84 (s, 1H), 8.72 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.92 (d, J = 10.9Hz, 1H), 4.26-4.16 (m, 1H), 3.51 (s, 3H), 1.20 (d, J = 5.5 Hz, 4H). 41395% 3-24

OMe

¹H NMR (400 MHz, DMSO) δ 14.47 (s, 1H), 8.89 (t, J = 1.3 Hz, 1H), 8.86(d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H),7.75 (d, J = 1.2 Hz, 1H), 7.63 (t, J = 1.3 Hz, 1H), 5.31-4.93 (dtd, J =64.0, 5.5, 3.3 Hz, 1H), 4.26- 4.12 (dt, J = 8.9, 5.4 Hz, 1H), 3.54 (s,3H), 1.93-1.49 (m, 2H). 446 98% 3-25

Me

¹H NMR (400 MHz, CDCl₃) δ 14.07 (s, 1H), 8.55 (s, 1H), 8.14 (d, J = 8.4Hz, 1H), 8.00 (d, J = 17.0 Hz, 1H), 7.66 (dd, J = 11.6, 4.8 Hz, 2H),7.49 (d, J = 4.4 Hz, 1H), 7.13-7.03 (m, 2H), 7.01 (d, J = 0.8 Hz, 1H),5.22 (s, 1H), 1.72 (s, 3H). 484 98% 3-26

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 9.09 (s, 1H),8.93 (s, 1H), 8.58 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H),4.46-4.36 (m, 1H), 2.70 (s, 3H), 2.64 (s, 3H), 1.25 (d, J = 6.2 Hz, 2H),1.09 (s, 2H). 393 98% 3-27

Me

¹H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 8.90 (d, J = 3.0 Hz, 1H), 8.76(s, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.57 (s,1H), 5.16 (d, J = 64.5 Hz, 1H), 4.44- 4.33 (m, 1H), 2.65 (s, 3H),1.83-1.68 (m, 1H), 1.62 (m, 1H). 430 98% 3-28

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 9.63 (s, 1H),8.94 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H),4.50-4.37 (m, 1H), 2.73 (s, 3H), 1.24 (t, J = 9.6 Hz, 2H), 1.12 (s, 2H).447 98% 3-29

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 8.94 (s, 1H), 8.74(s, 1H), 8.63 (s, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 4.51 (s,2H), 4.46-4.36 (m, 1H), 2.71 (s, 3H), 1.26 (d, J = 6.8 Hz, 2H), 1.09 (s,2H). 408 95% 3-30

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.58 (s, 1H), 9.37 (s, 1H),8.84 (s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H),4.29-4.18 (m, 1H), 3.51 (s, 3H), 1.20 (d, J = 5.4 Hz, 4H). 429 96% 3-31

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 8.99 (s, 1H), 8.89(s, 1H), 8.14-8.01 (m, 2H), 7.54 (d, J = 9.8 Hz, 1H), 4.49 (s, 2H), 2.77(s, 3H), 1.30 (s, 2H), 1.14 (s, 2H). 379 88% 3-32

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.92 (s, 1H),8.83 (s, 1H), 8.00 (s, 2H), 7.57 (d, J = 9.3 Hz, 1H), 4.23 (s, 1H), 3.51(s, 3H), 1.18 (s, 4H). 395 95% 3-33

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.74 (s, 1H), 8.48(s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 4.39 (s, 2H), 2.64 (s,3H), 1.29 (s, 2H), 1.07 (s, 2H). 379 99% 3-34

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.02-14.73 (m, 1H), 9.01 (s,1H), 8.10 (s, 3H), 7.54 (s, 1H), 4.51 (s, 1H), 1.33 (s, 2H), 1.18 (s,2H). 379 95% 3-35

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 14.19 (s, 1H),8.93 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 4.42 (s, 1H), 2.64 (s, 3H), 1.22 (m, 2H), 1.12 (m, 2H). 423 98%3-36

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.97 (s, 1H),8.10 (s, 1H) 8.01 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.48 (s, 1H), 4.46(s, 1H), 2.70 (s, 2H), 1.30 (s, 2H), 1.12 (s, 2H). 393 98% 3-37

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83 (s, 1H), 13.45 (b, 1H),8.98 (s, 1H), 8.26 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.90 (s, 1H), 7.78(d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.46 (s, 1H), 2.68 (s,3H), 1.31 (d, J = 5.7 Hz, 2H), 1.14 (s, 2H). 378 92% 3-38

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 13.83 (s, 1H),8.91 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.53(s, 1H), 4.46-4.34 (m, 1H), 2.63 (s, 3H), 1.25 (d, J = 6.9 Hz, 2H), 1.09(s, 2H). 412 98% 3-39

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 14.27 (s, 1H),8.90 (s, 1H), 8.62 (d, J = 10.6 Hz, 3H), 8.07 (d, J = 9.1 Hz, 1H), 4.31(s, 1H), 3.44 (s, 3H), 1.26 (s, 4H). 439 95% 3-40

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.77 (s, 1H), 13.23 (s, 1H),8.91 (s, 1H), 8.49 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.67 (s, 1H), 7.25 (d, J = 7.9 Hz, 1H), 4.40 (s, 1H), 2.61 (s,2H), 1.25 (s, 2H), 1.09 (s, 2H). 378 98% 3-41

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 9.52 (s, 1H),8.92 (s, 1H), 8.30 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.8Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.25 (d,J = 5.9 Hz, 2H), 1.08 (s, 2H). 395 95% 3-42

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.77 (s, 1H), 11.96 (s, 1H),8.92 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.61(s, 1H), 6.57 (s, 1H), 4.41 (s, 1H), 2.64 (s, 3H), 1.26 (d, J = 6.1 Hz,2H), 1.09 (s, 2H). 378 98% 3-43

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.48 (s, 1H), 8.97-6.90(d, J = 2.7 Hz, 2H), 8.63-8.55 (s, 1H), 8.07-7.97 (t, J = 9.2 Hz, 2H),7.69- 7.58 (m, 1H), 4.48-4.39 (s, 2H), 2.73-2.65 (s, 3H), 1.27-1.20 (m,2H), 1.14-1.06 (s, 2H). 403 95% 3-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.02-9.98 (s, 1H), 9.48-9.43(s, 1H), 8.95-8.90 (s, 1H), 8.67-8.62 (s, 1H), 8.12-8.07 (d, J = 9.2 Hz,1H), 8.07-8.01 (d, J = 8.9 Hz, 1H), 7.82-7.75 (dd, J = 9.4, 1.7 Hz, 1H),4.48-4.36 (s, 1H), 2.72-2.67 (s, 3H), 1.25-1.21 (t, J = 3.8 Hz, 2H),1.14-1.06 (m, 2H). 406 90% 3-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.83 (s, 1H). 8.40(s, 1H), 8.09-8.05 (dd, J = 9.2, 1.0 Hz, 1H), 8.05-8.00 (d, J = 8.7 Hz,1H), 7.81-7.72 (dd, J = 9.3, 1.7 Hz, 1H), 5.35-5.16 (s, 1H), 4.53-4.33(m, 1H), 2.75- 2.64 (s, 3H), 1.28-1.20 (d, J = 6.2 Hz, 2H), 1.15-1.03(d, J = 3.8 Hz, 2H). 402 98% 3-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70-14.56 (s, 1H), 9.23-9.15(m, 1H), 8.99-8.89 (s, 1H), 8.72-8.65 (s, 1H), 8.08-7.99 (d, J = 8.8 Hz,1H), 7.84-7.77 (s, 1H), 7.16-7.04 (m, 1H), 6.93-6.82 (m, 1H) 5.82-5.69(dd, J = 11.2, 1.6 Hz, 1H), 4.49-4.36 (t, J = 3.5 Hz, 1H), 2.75-2.68 (s,3H), 1.33-1.19 (t, J = 6.5 Hz, 2H), 1.16-1.03 (s, 2H). 405 97% 3-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.48 (s, 1H), 8.96-8.91(s, 4H), 8.86-8.79 (s, 4H), 8.64- 8.56 (d, J = 2.3 Hz, 4H), 8.06-7.99(d, J = 8.8 Hz, 4H), 7.86-7.79 (d, J = 9.4 Hz, 4H), 7.52- 7.43 (s, 3H),4.48-4.37 (s, 1H), 2.74-2.67 (s, 12H), 1.29-1.20 (d, J = 6.8 Hz, 9H),1.11-1.01 (t, J = 3.0 Hz, 6H). 422 96% 3-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.48 (s, 1H), 8.95-8.89(s, 1H), 8.84-8.78 (s, 1H), 8.63- 8.58 (s, 1H), 8.05-8.00 (d, J = 8.8Hz, 1H), 7.90-7.84 (d, J = 9.4 Hz, 1H), 7.53-7.45 (d, J = 9.3 Hz, 1H),4.47-4.40 (s, 1H), 2.73-2.68 (s, 3H), 1.27-1.21 (d, J = 6.6 Hz, 2H),1.12-1.02 (s, 2H). 446 90% 3-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.66 (s, 1H),8.06-7.99 (d, J = 8.7 Hz, 1H), 7.99-7.95 (s, 1H), 7.94-7.88 (d, J = 9.3Hz, 1H), 7.55-7.47 (dd, J = 9.3, 1.6 Hz, 1H), 4.52- 4.32 (m, 1H),2.77-2.61 (s, 3H), 1.33-1.17 (d, J = 6.6 Hz, 2H), 1.19-1.05 (t, J = 3.3Hz, 2H). 412 98% 3-50

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.60 (s, 1H),8.06-8.00 (d, J = 8.7 Hz, 1H), 8.00-7.96 (s, 1H), 7.92-7.86 (d, J = 9.3Hz, 1H), 7.56-7.48 (d, J = 9.4 Hz, 1H), 4.55-4.26 (m, 1H), 2.81-2.60 (s,3H), 1.37-1.21 (d, J = 6.5 Hz, 2H), 1.15-1.05 (m, 2H). 456, 458 97% 3-51

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71-14.62 (s, 1H), 8.96-8.88(s, 1H), 8.83-8.75 (s, 1H), 8.25-8.16 (d, J = 7.5 Hz, 2H), 8.15-8.07 (s,1H), 8.07-7.97 (d, J = 8.8 HZ, 1H), 7.77- 7.71 (s, 1H), 7.57-7.42 (m,4H), 4.50-4.33 (s, 1H), 2.82-2.71 (s, 3H), 1.31-1.22 (d, J = 6.7 Hz,2H), 1.15-1.04 (s, 2H). 454 99% 3-52

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71-14.60 (s,1H), 8.95-8.88(s,1H), 8.73-8.65 (s, 1H), 8.10-7.96 (m, 2H), 7.74-7.68 (s, 1H), 7.40-7.32 (s, 1H), 7.11-7.02 (m, 1H), 6.96-6.83 (m, 1H), 5.70-5.60 (dd, J =11.2, 2.0 Hz, 1H), 4.47-4.38 (t, J = 3.5 Hz, 1H), 2.78-2.69 (s, 3H),1.31-1.20 (d, J = 6.9 Hz, 2H), 1.14- 1.01 (s, 2H). 405 93% 3-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71-14.60 (s, 1H), 8.95-8.88(s, 1H), 8.73-8.65 (s, 1H), 8.10-7.96 (m, 2H), 7.74-7.68 (s, 1H), 7.40-7.32 (s, 1H), 7.11-7.02 (m, 1H), 6.96-6.83 (m, 1H), 5.70-5.60 (dd, J =11.2, 2.0 Hz, 1H), 4.47-4.38 (t, J = 3.5 Hz, 1H), 2.78-2.69 (s, 3H),1.31-1.20 (d, J = 6.9 Hz, 2H), 1.14-1.01 (s, 2H). 403 95% 3-54

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.39 (s, 1H), 9.20-9.07(d, J = 7.0 Hz, 1H), 8.95- 8.90 (s, 1H), 8.67-8.60 (s, 1H), 8.08-8.00(m, 2H), 7.32-7.24 (m, 1H), 4.47-4.36 (s, 1H), 2.75-2.61 (s, 3H),1.30-1.19 (m, 2H), 1.15- 1.03 (q, J = 3.8, 3.1 Hz, 2H). 379 98% 3-55

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.36 (s, 1H), 9.68-9.65(d, J = 1.5 Hz, 1H), 8.95- 8.92 (s, 1H), 8.84-8.81 (s, 1H), 8.63-8.59(d, J = 1.5 Hz, 1H), 8.06-8.01 (d, J = 8.8 Hz, 1H), 4.46-4.39 (s, 1H),2.76-2.69 (s, 3H), 1.30-1.20 (m, 2H), 1.14-1.05 (s, 2H). 404 98% 3-56

OMe

¹H NMR (400 MHz, DMSO) δ 14.73-14.06 (s, 1H), 9.21-9.18 (m, 1H),6.87-8.83 (d, J = 1.86 Hz, 1H), 8.32-8.27 (d, J = 1.33 Hz, 1H),8.20-8.16 (s, 1H), 8.04-7.97 (d, J = 9.06 Hz, 1H), 7.87-7.80 (d, J =1.20 Hz, 1H), 5.31-4.87 (m, 1H), 4.32-4.12 (m, 1H), 3.67-3.47 (s, 3H),1.95-1.56 (m, 2H). 437 98% 3-57

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H), 8.83 (s, 1H),8.77 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.73(d, J = 1.0 Hz, 1H), 7.40 (d, J = 11.8 Hz, 1H), 4.46-4.08 (m, 1H), 3.51(d, J = 10.5 Hz, 3H), 1.19 (d, J = 6.9 Hz, 4H). 412 90% 3-58

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.57 (s, 1H), 9.82-9.48(s, 2H), 9.01-8.84 (d, J = 2.6 Hz, 1H), 8.05-7.90 (dd, J = 8.5, 2.7 Hz,1H), 7.65- 7.57 (d, J = 7.5 Hz, 1H), 7.51-7.46 (s, 1H), 7.45-7.36 (d, J= 7.7 Hz, 1H), 4.72-4.50 (s, 4H), 4.47-4.28 (d, J = 6.8 Hz, 1H),2.64-2.53 (d, J = 2.7 Hz, 3H), 1.31-1.14 (d, J = 6.1 Hz, 2H), 1.14-0.96(s, 2H). 379 95% 3-59

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95-8.83 (d, J = 2.4 Hz, 1H),7.98-7.86 (d, J = 8.8 Hz, 1H), 7.25- 7.15 (s, 1H), 7.14-7.01 (d, J = 7.9Hz, 1H), 6.97- 6.81 (d, J = 7.9 Hz, 1H), 3.65-3.50 (m, 2H), 4.45-4.29(dp, J = 9.2, 4.7, 3.9 Hz, 1H), 3.16- 2.99 (t, J = 8.4 Hz, 2H),2.65-2.56 (s, 3H), 1.28- 1.16 (d, J = 6.6 Hz, 3H), 1.12-0.97 (m, 2H).379 99% 3-60

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.39 (m, 1H), 12.95-12.53(s, 2H), 9.03-8.82 (t, J = 1.9 Hz, 1H), 8.73-8.47 (s, 2H), 8.10-7.90 (d,J = 8.4 Hz, 1H), 7.62-7.44 (m, 1H), 4.51-4.23 (m, 1H), 7.44-7.31 (s,1H), 7.31-7.11 (d, J = 8.6 Hz, 1H), 2.65-2.55 (s, 3H), 1.30-1.16 (m,2H), 1.16-0.96 (s, 2H). 393 90% 3-61

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.17-9.06 (d, J = 2.8 Hz, 1H),8.30-8.15 (m, 1H), 7.94-7.80 (m, 2H), 7.65-7.49 (dt, J = 7.5, 3.3 Hz,2H), 4.47- 4.32 (d, J = 6.9 Hz, 1H), 2.96-2.81 (d, J = 2.8 Hz, 3H),1.43-1.27 (dd, J = 10.8, 4.5 Hz, 2H), 1.21-1.05 (s, 2H). 378 100% 3-62

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63-14.42 (s, 1H), 8.99-8.89(s, 1H), 8.33-8.25 (d, J = 7.8 Hz, 1H), 8.25-8.18 (d, J = 8.0 Hz, 1H),8.14-8.05 (d, J = 8.7 Hz, 1H), 7.71-7.56 (dt, J = 22.8, 7.4 Hz, 2H),4.51-4.31 (s, 1H), 2.85-2.70 (s, 3H), 1.30- 1.20 (d, J = 7.0 Hz, 2H),1.13-0.97 (s, 2H). 395 100% 3-63

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.28 (s, 2H), 9.04-8.32(t, J = 2.3 Hz, 1H), 8.05-7.98 (d, J = 8.3 Hz, 1H), 7.98-7.92 (dd, J =10.5, 2.5 Hz, 1H), 7.90-7.83 (s, 1H), 7.56-7.47 (d, J = 8.2 Hz, 1H),4.46-4.34 (t, J = 6.3 Hz, 1H), 2.87-2.78 (t, J = 2.1 Hz, 3H), 2.64-2.55(s, 3H), 1.29-1.16 (m, 2H), 1.16-1.03 (s, 2H). 392 100% 3-64

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.28 (s, 2H), 9.04-8.82(t, J = 2.3 Hz, 1H), 8.05-7.98 (d, J = 8.3 Hz, 1H), 7.98-7.92 (dd, J =10.5, 2.5 Hz, 1H), 7.90-7.83 (s, 1H), 7.56-7.47 (d, J = 8.2 Hz, 1H),4.46-4.34 (t, J = 6.3 Hz, 1H), 2.87-2.78 (t, J = 2.1 Hz, 3H), 2.64-2.55(m, 6H), 1.29-1.16 (m, 2H), 1.16-1.03 (s, 2H). 421 100% 3-65

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.05-14.35 (m, 1H), 10.46-9.91(m, 1H), 9.02-8.80 (s, 1H), 8.80-8.47 (d, J = 15.2 Hz, 1H), 8.12-7.64(m, 3H), 7.44-7.25 (dd, J = 23.7, 8.0 Hz, 1H), 4.84- 4.63 (d, J = 8.8Hz, 2H), 4.49-4.32 (s, 1H), 3.01-2.77 (d, J = 17.9 Hz, 6H), 1.37-1.13(d, J = 6.9 Hz, 2H), 1.17-0.86 (s, 2H). 449 96% 3-66

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.97-14.24 (s, 2H), 9.14-8.97(m, 2H), 8.98-8.88 (s, 2H), 8.07- 7.89 (dd, J = 24.1, 8.9 Hz, 6H),7.86-7.79 (s, 1H), 7.52-7.37 (t, J = 9.6 Hz, 3H), 4.57-4.31 (t, J = 6.8Hz, 5H), 2.66-2.55 (s, 7H), 1.60-1.40 (m, 7H), 1.30-1.16 (m, 2H),1.16-0.98 (s, 2H). 406 97% 3-67

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.97-14.24 (s, 2H), 9.14-8.97(m, 2H), 8.98-8.88 (s, 2H), 8.07- 7.89 (dd, J = 24.1, 8.9 Hz, 6H),7.86-7.79 (s, 1H), 7.52-7.37 (t, J = 9.6 Hz, 3H), 4.57-4.31 (t, J = 6.8Hz, 5H), 2.66-2.55 (s, 3H), 1.60-1.40 (m, 7H), 1.30-1.16 (m, 2H),1.16-0.96 (s, 2H). 392 100% 3-68

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95-8.91 (s, 1H), 8.65-8.59 (s,1H), 8.31-8.25 (s, 1H), 8.23- 8.17 (s, 1H), 8.05-7.98 (m, 1H), 4.48-4.35(s, 1H), 2.68-2.61 (s, 3H), 1.30-1.22 (s, 2H), 1.16- 1.06 (s, 2H). 42397% 3-69

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.96-14.48 (m, 1H), 10.94-10.65(d, J = 25.6 Hz, 2H), 9.01- 8.77 (m, 1H), 8.05-7.81 (d, J = 8.6 Hz, 1H),7.18-7.00 (d, J = 7.8 Hz, 1H), 7.00-6.78 (m, 2H), 4.47-4.25 (td, J =6.9, 3.6 Hz, 1H), 2.67- 2.54 (s, 3H), 1.27-1.10 (d, J = 6.3 Hz, 2H),1.14-0.88 (s, 2H). 394 94% 3-70

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.02-14.18 (s, 1H), 9.00-8.67(m, 2H), 8.12-7.68 (m, 3H), 7.49-7.25 (dd, J = 16.6, 8.2 Hz, 1H),5.04-4.75 (m, 1H), 4.62-4.23 (m, 9H), 3.77-3.55 (m, 2H), 3.57-3.23 (d, J= 7.0 Hz, 1H), 2.70-2.53 (s, 3H), 1.37-1.15 (t, J = 8.0 Hz, 2H),1.15-0.84 (td, J = 16.0, 7.8 Hz, 9H). 494 90% 3-71

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.45-14.13 (s, 1H), 11.09-10.85(s, 1H), 8.73-8.58 (d, J = 2.7 Hz, 1H), 7.85-7.61 (m, 2H), 7.31-7.15 (m,1H), 7.07-6.83 (m, 2H), 4.27-4.07 (s, 1H), 3.82-3.71 (d, J = 2.5 Hz,3H), 1.27-1.08 (m, 2H), 1.08- 0.86 (s, 2H). 408 93% 3-72

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.07-14.72 (s, 1H), 9.21-8.97(s, 1H), 8.95-8.73 (m, 1H), 8.41-8.14 (m, 1H), 8.12-7.95 (s, 1H),3.40-3.18 (m, 4H), 7.95-7.79 (d, J = 8.6 Hz, 1H), 7.79- 7.60 (dd, J =8.5, 3.9 Hz, 2H), 4.34-4.10 (d, J = 6.3 Hz, 1H), 1.30-1.02 (s, 4H). 37695% 3-73

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.68-10.51(s, 1H), 9.04-8.78 (m, 1H), 8.01-7.81 (m, 1H), 7.36-7.11 (m, 2H), 7.11-6.87 (dd, J = 7.8, 2.7 Hz, 1H), 4.47-4.29 (s, 1H), 3.72-3.47 (s, 2H),1.27-1.08 (m, 2H), 1.08-0.86 (s, 2H). 393 97% 3-74

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.68-10.51(s, 1H), 9.04-6.78 (m, 1H), 8.01-7.81 (m, 1H), 7.36-7.11 (m, 2H), 7.11-6.87 (dd, J = 7.8, 2.7 Hz, 1H), 4.47-4.29 (s, 1H), 3.72-3.47 (s, 2H),2.66-2.57 (d, J = 2.7 Hz, 3H), 2.55-2.45 (d, J = 3.4 Hz, 4H). 424 97%3-75

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.80-14.62 (m, 1H), 8.38-8.18(m, 1H), 8.03-7.83 (m, 1H), 8.96-8.82 (m, 1H), 7.77-7.59 (m, 1H), 7.37-7.22 (m, 1H), 4.48-4.29 (m, 1H), 3.24-3.08 (m, 2H), 3.94-3.70 (m, 2H),1.32-1.12 (m, 2H), 1.12-0.86 (m, 2H). 394 100% 3-76

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.11-14.26 (d, J = 53.0 Hz,1H), 10.22-9.45 (m, 1H), 9.01-8.84 (m, 1H), 8.77-8.58 (s, 1H), 8.09-7.92(d, J = 8.5 Hz, 1H), 7.88-7.68 (s, 1H), 7.51-7.33 (s, 1H), 4.84-4.58 (s,2H), 4.53-4.25 (s, 1H), 2.96-2.72 (s, 6H), 2.72-2.56 (s, 3H), 1.34-1.17(d, J = 6.5 Hz, 2H), 1.17-0.93 (d, J = 10.1 Hz, 2H). 435 94% 3-77

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.87-14.59 (s, 1H), 12.20-12.00(s, 1H), 9.01-8.79 (s, 1H), 8.09- 7.83 (d, J = 8.6 Hz, 1H), 7.74-7.59(s, 1H), 7.39- 7.20 (m, 2H), 4.48-4.31 (s, 1H), 2.72-2.56 (s, 3H),1.36-1.12 (d, J = 6.9 Hz, 2H), 1.12-0.79 (s, 2H). 411 98% 3-78

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.68-10.51(s, 1H), 9.04-8.78 (m, 1H), 8.01-7.81 (m, 1H), 7.36-7.11 (m, 2H),7.11-6.87 (dd, J = 7.8, 2.7 Hz, 1H), 4.47-4.29 (s, 1H), 3.72-3.47 (s,2H), 1.27-1.08 (m, 2H), 1.08-0.86 (s, 2H). 393 95% 3-79

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82-14.60 (s, 1H), 11.50-11.28(s, 1H), 8.99-8.81 (s, 1H), 8.09-7.90 (m, 2H), 7.66-7.53 (d, J = 1.1 Hz,1H), 6.91-6.78 (s, 1H), 6.17-5.99 (d, J = 15.7 Hz, 1H), 5.38-5.23 (d, J= 9.0 Hz, 1H), 4.48-4.31 (dd, J = 8.4, 4.4 Hz, 1H), 3.61-3.41 (s, 1H),2.71-2.56 (s, 3H), 1.32- 1.16 (s, 2H), 1.14-0.97 (s, 2H). 421 97% 3-80

MeO Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82-14.60 (s, 1H),11.50-11.28 (s, 1H), 8.99-8.81 (s, 1H), 8.09-7.90 (m, 2H), 7.66-7.53 (d,J = 1.1 Hz, 1H), 6.91-6.78 (s, 1H), 6.17-5.99 (d, J = 15.7 Hz, 1H),5.38-5.23 (d, J = 9.0 Hz, 1H), 4.48-4.31 (dd, J = 8.4, 4.4 Hz, 1H),3.61- 3.41 (s, 1H), 2.71-2.56 (s, 3H), 1.14-0.97 (s, 4H). 437 90% 3-81

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.95-10.69(s, 1H), 9.06-8.79 (s, 2H), 8.05-7.90 (d, J = 8.7 Hz, 1H), 7.28-7.09 (s,1H), 6.65-6.63 (s, 1H), 4.46 -4.29 (tt, J = 7.4, 4.0 Hz, 1H), 2.72-2.54(s, 3H), 1.32-1.14 (d, J = 5.8 Hz, 2H), 1.14-0.97 (d, J = 3.8 Hz, 2H).394 94% 3-82

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.89-14.50 (s, 2H),11.09-10.63 (s, 1H), 9.21-8.97 (s, 1H), 8.97-8.73 (s, 1H), 8.07-7.85 (m,1H), 3.48-3.31 (m, 5H), 7.42- 7.26 (m, 1H), 7.04-6.87 (m, 1H), 4.31-4.13(p, J = 5.6 Hz, 1H), 2.72-2.54 (s, 3H), 1.27-1.01 (d, J = 5.6 Hz, 4H).410 98% 3-83

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.05-14.39 (s, 1H),13.02-12.32 (s, 1H), 8.97-8.77 (s, 1H), 8.47-8.20 (s, 1H), 7.85-7.39 (m,2H), 7.33-6.98 (d, J = 8.0 Hz, 1H), 4.47-4.23 (s, 1H), 2.74-2.52 (s,3H), 1.34-1.13 (m, 2H), 1.13-0.71 (s, 2H). 428 100% 3-84

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (d, J = 8.7 Hz, 1H), 8.91(s, 1H), 8.13 (s, 1H), 7.99 (t, J = 11.1 Hz, 1H), 7.78 (t, J = 13.2 Hz,1H), 7.72 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.07 (s, 1H), 4.40 (m, 1H),2.61 (s, 3H), 1.24 (d, J = 5.7 Hz, 2H), 1.08 (s, 2H). 378 98% 3-85

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.90 (s, 1H),8.21 (d, J =8.0 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.90(s, 1H), 7.56 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 4.38 (s, 1H), 2.65 (s,3H), 1.17 (m, 2H), 1.06 (m, 2H). 394 98% 3-86

¹H NMR (400 MHz, DMSO) δ 15.38-14.22 (s, 1H), 9.14-9.08 (s, 1H),9.00-8.94 (s, 1H), 8.32-8.24 (s, 1H), 7.93-7.90 (s, 1H), 7.90-7.86 (s,1H), 7.83-7.76 (d, J = 9.72 Hz, 1H), 5.07-4.96 (d, J = 6.74 Hz, 1H),4.65-4.56 (d, J = 11.26 Hz, 1H), 4.53-4.43 (d, J = 9.86 Hz, 1H),1.54-1.46 (d, J = 6.76 Hz, 3H). 414 99% 3-87

¹H NMR (400 MHz, DMSO) δ 14.87 (s, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.27(d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.63 (m,2H), 4.46- 4.36 (m, 1H), 2.76 (s, 3H), 1.29 (d, J = 6.5 Hz, 2H), 1.08(t, J = 7.4 Hz, 2H). 394 99%

TABLE 4

Com- pound MS No. R³ = NMR (MH⁺) HPLC 4-1

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 11.38 (s, 1H), 8.70 (s, 1H),7.78 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 8.1 Hz,1H), 7.00-6.92 (m, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.51 (s, 1H),4.24-4.16 (m, 1H), 2.56 (s, 3H), 1.03 (dd, J = 12.0, 4.6 Hz, 2H), 0.86(d, J = 7.4 Hz, 2H). 377 95% 4-2

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.59 (s, 1H), 8.92 (s, 1H),8.00 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.0 Hz,1H), 7.19 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.73 (s, 1H),4.42 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.1 Hz, 2H), 1.07 (s, 2H). 377100% 4-3

¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.93 (s, 1H), 8.05 (d, J = 8.6Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.30-7.24(m, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.68 (s, 1H), 4.41 (s, 1H), 3.58 (s,3H), 2.65 (s, 3H), 1.24 (s, 4H). 391 98% 4-4

¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 11.36 (s, 1H), 8.90 (s, 1H),7.95 (d, J = 7.8 Hz, 1H), 7.57 (s, 3H), 7.46 (s, 1H), 7.07 (d, J = 8.5Hz, 1H), 6.53 (s, 1H), 4.39 (s, 1H), 2.62 (s, 3H), 1.24 (s, 2H), 1.09(d, J = 18.8 Hz, 2H). 377 87% 4-5

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.55 (s, 1H), 8.92 (s, 1H),8.00 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.4 Hz,1H), 6.87 (d, J = 6.9 Hz, 1H), 6.75 (s, 1H), 4.42 (s, 1H), 2.79 (s, 3H),2.09 (s, 1.28 (d, J = 6.0 Hz, 2H), 1.07 (s, 2H). 391 90% 4-6

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.43 (s, 1H), 8.91 (s, 1H),7.99 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 6.6 Hz, 1H), 7.13 (s, 1H), 6.84(d, J = 8.7 Hz, 1H), 6.63 (s, 1H), 4.41 (s, 1H), 3.78 (s, 4H), 2.77 (s,3H), 1.26 (d, J = 5.7 Hz, 2H), 1.07 (s, 2H). 407 92.3% 4-9

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 12.23 (d, J = 30.1 Hz, 1H), 8.93(s, 1H), 8.20 (d, J = 11.8 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 6.87 (d,J = 26.1 Hz, 1H), 4.38 (d, J = 31.7 Hz, 1H), 2.74 (d, J = 19.6 Hz, 3H),1.24 (d, J = 8.9 Hz, 2H), 1.07 (s, 2H). 402 92.8% 4-10

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.70 (s, 1H), 8.92 (s, 1H),8.00 (d, J = 8.9 Hz, 1H), 7.52-7.44 (m, 1H), 7.41 (d, J = 9.8 Hz, 1H),7.04 (t, J = 9.3 Hz, 1H), 6.72 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26(d, J = 6.4 Hz, 2H), 1.07 (s, 2H). 395 89.7% 4-11

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 11.98 (s, 1H), 8.93 (s, 1H),8.02 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.19 (q, J = 7.8 Hz,2H), 6.76 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.2 Hz, 2H),1.08 (s, 2H). 411 97% 4-12

¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.30 (s, 1H), 8.93 (s, 1H),8.04 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 7.36(s, 1H), 6.91 (s, 1H), 4.43 (s, 1H), 2.78 (s, 3H), 1.28 (s, 2H), 1.09(s, 2H). 402 99% 4-13

¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 11.93 (s, 1H), 8.92 (s, 1H),8.01 (d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 6.5 Hz,1H), 6.87 (t, J = 8.9 Hz, 1H), 6.80 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H),1.27 (d, J = 6.4 Hz, 2H), 1.07 (s, 2H). 395 87% 4-14

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.43 (s, 1H), 8.92 (s, 1H),8.00 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 6.98 (s, 2H), 6.67 (s, 1H), 4.42(s, 1H), 2.77 (s, 3H), 1.26 (d, J = 6.3 Hz, 2H), 1.09 (s, 2H). 391 92.7%4-15

¹H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.02 (s, 1H), 8.04 (s, 1H), 7.55(s, 2H), 7.29 (s, 1H), 6.96 (s, 1H), 6.67 (s, 1H), 2.85 (s, 3H), 2.47(s, 3H), 1.34 (s, 2H), 1.09 (s, 2H). 391 99% 4-16

¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.41 (s, 1H), 8.93 (s, 1H),8.69 (s, 1H), 8.07 (d, J = 13.8 Hz. 2H), 7.67 (s, 1H), 7.05 (s, 1H),4.42 (s, 1H), 2.78 (s, 3H), 1.26 (s, 2H), 1.08 (s, 2H). 422 100% 4-17

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.70 (s, 1H), 8.92 (s, 1H),8.00 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.24 (d, J = 10.1 Hz, 1H), 6.96(t, J = 9.1 Hz, 1H), 6.76 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26 (d,J = 5.7 Hz, 2H), 1.07 (s, 2H). 395 88% 4-18

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 12.08 (s, 1H), 8.92 (s, 1H),8.01 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.04 (d, J = 9.3 Hz,2H), 6.79 (s, 1H), 4.42 (s, 1H), 2.76 (s, 3H), 1.26 (d, J = 6.2 Hz, 2H),1.08 (s, 2H). 395 89.1% 4-19

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 12.66 (s, 1H), 11.98 (s, 1H),8.93 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.70 (q, J = 8.2Hz, 2H), 6.83 (s, 1H), 4.43 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.2 Hz,2H), 1.08 (s, 2H). 421 100% 4-20

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 11.78 (s, 1H), 8.92 (s, 1H),8.01 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 7.10(d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26 (d,J = 6.1 Hz, 2H), 1.07 (s, 2H). 411 90% 4-21

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 12.71 (s, 1H), 8.92 (s, 1H),8.15 (s, 1H), 8.04 (d, J = 9.4 Hz, 2H), 7.43 (s, 1H), 7.29 (s, 1H), 4.42(s, 1H), 2.79 (s, 3H), 1.27 (s, 2H), 1.08 (s, 2H). 422 97% 4-22

¹H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.55(d, J = 12.6 Hz, 2H), 7.47 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.77 (s,1H), 6.57 (d, J = 7.9 Hz, 1H), 6.51 (s, 1H), 4.29 (s, 1H), 2.78 (s, 3H),1.38-1.24 (m, 2H), 1.20 (s, 2H). 393 90% 4-23

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 11.82 (s, 1H), 8.92 (s, 1H),8.01 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.19(d, J = 9.4 Hz, 1H), 6.73 (s, 1H), 4.42 (s, 1H), 2.76 (s, 3H), 1.26 (d,J = 6.1 Hz, 2H), 1.07 (s, 2H). 411 90% 4-24

¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 11.61 (s, 1H), 8.95 (d, J = 9.5Hz, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.67 (d, J = 9.1 Hz, 1H), 6.52 (s,1H), 4.43 (s, 1H), 2.78 (s, 3H), 1.25 (s, 2H), 1.08 (s, 2H). 422 90%4-25

¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 11.31 (s, 1H), 8.91 (s, 1H),7.97 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.41(s, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.53 (s, 1H), 4.40 (s, 1H), 2.63 (s,3H), 1.24 (s, 2H), 1.08 (s, 2H). 377 100% 4-26

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 12.37 (s, 1H), 8.93 (s, 1H),8.19 (t, J = 9.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.00(s, 1H), 4.43 (s, 1H), 2.75 (s, 3H), 1.24 (s, 2H), 1.11 (s, 2H). 422 99%4-27

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.45 (s, 1H), 9.17 (s, 1H),8.92 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.77 (s, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.24 (s, 1H), 6.64 (s, 1H), 4.42 (s, 1H), 2.77 (s, 2H), 1.46(d, J = 29.9 Hz, 9H), 1.25 (s, 2H), 1.06 (s, 2H). 492 100% 4-28

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.94 (s, 1H), 9.97 (s, 2H),8.93 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.19-7.13 (m, 1H), 6.84 (s, 1H), 4.42 (s, 2H), 2.76 (s, 3H),1.14- 1.00 (m, 4H). 392 94% 4-29

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.94 (s, 1H), 9.97 (s, 2H),8.93 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.19-7.13 (m, 1H), 6.84 (s, 1H), 4.42 (s, 2H), 2.76 (s, 3H),1.14- 1.00 (m, 4H). 391 100% 4-30

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.38 (s, 1H), 9.33 (s, 1H),8.91 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.81 (s, 1H), 7.48 (d, J = 8.3Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.64 (s, 1H), 4.42 (s, 1H), 2.78 (s,3H), 1.51 (s, 10H), 1.25 (d, J = 8.9 Hz, 2H), 1.08 (dd, J = 14.0, 6.3Hz, 2H). 492 97% 4-31

¹H NMR (400 MHz, DMSO) δ 14.31 (s, 1H), 11.68 (s, 1H), 8.94 (s, 1H),8.17 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.1 Hz,1H), 7.21 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.80 (s, 1H),4.44 (s, 1H), 1.25 (d, J = 6.4 Hz, 2H), 1.12 (s, 2H). 397 100% 4-32

¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.74 (s, 1H), 9.35 (s, 2H),8.92 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.34(s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 4.42 (s, 1H), 2.78 (s,3H), 1.27 (d, J = 5.6 Hz, 3H), 1.06 (s, 2H). 392 97% 4-33

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.56 (s, 1H), 9.17 (s, 1H),8.93 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.46 (s, 2H), 7.12 (d, J = 20.9Hz, 2H), 5.18-4.56 (m, 1H), 4.44 (s, 1H), 2.80 (s, 3H), 1.24 (s, 2H),1.07 (s, 2H). 492 91% 4-34

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.77 (s, 1H), 8.93 (s, 1H),8.01 (d, J = 6.4 Hz, 1H), 7.23-7.03 (m, 2H), 6.88(s, 1H), 6.76 (d, J =6.4 Hz, 1H), 4.43 (m, 1H), 2.77(s, 3H), 1.24 (d, J = 6.6 Hz, 2H), 1.12(s, 2H). 392 99% 4-35

¹H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 11.79 (s, 1H), 8.94 (s, 1H),8.17 (d, J = 8.8 Hz, 1H), 7.56-7.38 (m, 2H), 7.06 (t, J = 8.8 Hz, 1H),6.79 (s, 1H), 4.44 (s, 1H), 1.24 (d, J = 6.6 Hz, 2H), 1.12 (s, 2H). 41591% 4-36

¹H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 12.16 (s, 1H), 8.95 (s, 1H),8.18 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 4.2 Hz, 1H), 7.05 (d, J = 8.5 Hz,2H), 6.85 (s, 1H), 4.43 (s, 1H), 1.24 (s, 2H), 1.13 (s, 2H). 415 95%4-37

¹H NMR (400 MHz, DMSO) δ 14.26 (s, 1H), 12.07 (s, 1H), 8.95 (s, 1H),8.19 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.29-7.07 (m, 2H),6.81 (s, 1H), 4.44 (s, 1H), 1.25 (s, 2H), 1.13 (s, 2H). 431 95% 4-38

¹H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 12.04 (s, 1H), 8.95 (s, 1H),8.19 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H),6.93-6.81 (m, 2H), 4.44 (s, 1H), 1.24 (s, 2H), 1.13 (s, 2H). 415 87%4-39

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.66 (s, 1H), 10.06 (s, 1H),8.92 (s, 1H), 8.02 (s, 3H), 7.46 (s, 1H), 7.31 (s, 1H), 7.19 (s, 1H),7.06 (s, 1H), 6.90 (s, 1H), 4.42 (s, 1H), 3.85 (s, 3H), 2.79 (s, 3H),1.26 (s, 2H), 1.07 (s, 2H). 526 95.6% 4-40

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.62 (s, 1H), 10.05 (s, 1H),8.93 (s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H),7.28-6.87 (m, 6H), 4.42 (s, 1H), 3.75 (s, 3H), 2.68 (s, 3H), 1.25 (d, J= 9.3 Hz, 2H), 1.05 (d, J = 18.8 Hz, 2H) 562 96% 4-41

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.66 (s, 1H), 9.62 (s, 1H),8.93 (s, 1H), 6.02 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.21 (s, 1H), 7.12(s, 1H), 7.04 (s, 1H), 4.44 (s, 1H) 3.05 (s, 1H), 2.82 (d, J = 25.3 Hz,3H), 1.12 (d, J = 24.4 Hz, 10H). 462 87% 4-42

¹H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 9.18 (s, 1H), 8.08-7.63 (m, 2H),7.48 (s, 2H), 7.20 (s, 2H), 6.95 (s, 2H), 4.54 (s, 1H), 4.24 (s, 2H),2.81 (s, 3H), 1.29 (s, 2H), 1.06 (s, 2H). 406 97% 4-43

¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 11.70 (s, 1H), 8.98 (s, 1H),8.06 (d, J = 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.20(s, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.91 (s, 1H), 4.49 (s, 3H), 2.84 (s,3H), 1.46 (s, 9H), 1.30 (s, 2H), 1.13 (s, 2H). 506 98% 4-44

¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 12.92 (s, 1H), 8.92 (s, 1H),8.79 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.3Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.25 (d,J = 5.7 Hz, 2H), 1.10 (s, 2H). 422 100% 4-45

¹H NMR (400 MHz, DMSO) δ 11.65 (s, 1H), 9.57 (s, 1H), 8.82 (s, 1H), 7.93(d, J = 8.3 Hz, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.19 (s, 1H), 7.09 (s,1H), 7.00 (s, 1H), 4.32 (s, 1H), 2.72 (d, J = 18.9 Hz, 3H), 1.89-1.77(m, 5H), 1.65 (s, 1H), 1.45 (d, J = 10.5 Hz, 2H), 1.35-1.16 (m, 6H),0.97 (s, 2H). 502 89% 4-46

¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.94 (s, 1H), 9.39 (s, 1H),8.92 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.28 (s, 1H), 7.15(s, 1H), 6.81 (s, 1H), 4.43 (s, 1H), 4.27-4.13 (m, 2H), 2.79 (s, 3H),2.33 (s, 1H), 2.17 (s, 1H), 1.59 (d, J = 14.2 Hz, 2H), 1.26 (s, 5H),1.07 (s, 2H), 0.85 (dd, J = 54.3, 14.6 Hz, 14H). 588 86.3% 4-47

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.74 (s, 1H), 10.60 (s, 1H),9.30 (s, 1H), 8.92 (s, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.9Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 6.7 Hz, 1H), 7.37 (d, J= 7.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 4.43 (s, 1H),2.79 (s, 3H), 1.25 (s, 2H), 1.07 (s, 2H). 565 96% 4-48

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.74 (s, 1H), 9.76 (s, 1H),8.93 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 6.6 Hz, 1H), 7.23-7.01 (m, 3H), 4.43 (s, 1H), 3.49 (d, J = 14.6 Hz, 1H), 3.06 (d, J = 14.8Hz, 1H), 2.37 (dd, J = 27.4, 15.5 Hz, 2H), 2.04 (s, 1H), 1.91 (d, J =17.7 Hz, 2H), 1.51 (d, J = 11.3 Hz, 1H), 1.41 (d, J = 10.3 Hz, 1H), 1.25(s, 2H), 1.09 (d, J = 11.8 Hz, 3H), 0.98 (s, 2H), 0.77 (d, J = 22.2 Hz,3H). 606 88% 4-49

¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.58 (s, 1H), 10.29 (s, 1H),8.91 (s, 1H), 8.40 (s, 1H), 8.05 (dd, J = 15.6, 8.6 Hz, 2H), 7.97 (s,2H), 7.83 (d, J = 8.2 Hz, 1H), 7.72- 7.56 (m, 2H), 7.18 (d, J = 8.0 Hz,1H), 7.04 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H),4.35 (s, 1H), 2.54 (s, 3H), 1.23 (s, 2H), 1.04 (s, 2H). 582 100% 4-50

¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.68 (s, 1H), 10.26 (s, 1H),8.92 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.29 (s, 1H), 7.19 (s, 1H),7.03 (s, 1H), 6.93 (s, 2H), 4.43 (s, 1H), 2.79 (s, 3H), 2.31 (s, 6H),2.10 (s, 3H), 1.24 (s, 2H), 1.07 (s, 2H). 538 90% 4-51

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.62 (s, 1H), 10.08 (s, 1H),8.93 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.18(d, J = 7.7 Hz, 2H), 7.02 (d, J = 18.7 Hz, 2H), 4.44 (s, 1H), 3.63 (s,3H), 2.76 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 536 99% 4-52

¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.68 (s, 1H), 9.29 (s, 1H),8.93 (s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.15(s, 2H), 7.02 (dd, J = 24.0, 8.3 Hz, 2H), 6.94 (s, 1H), 4.44 (s, 1H),3.91 (s, 3H), 2.80 (s, 3H), 1.25 (d, J = 15.5 Hz, 2H), 1.08 (s, 2H). 57596% 4-53

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.72 (s, 1H), 10.04 (s, 1H),8.94 (s, 1H), 8.02 (d, J = 10.3 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.24(s, 1H), 7.15 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H), 4.44 (s, 1H), 3.98 (s,2H), 3.76 (s, 2H), 3.43 (s, 2H), 3.07 (d, J = 24.3 Hz, 4H), 2.78 (s,3H), 2.69 (d, J = 10.9 Hz, 1H), 1.26 (s, 2H), 1.08 (s, 2H). 533 99% 4-54

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.72 (s, 1H), 10.03 (s, 1H),8.94 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.24 (s, 1H), 7.14(s, 1H), 7.03 (s, 1H), 5.33 (s, 1H), 4.43 (s, 1H), 4.03 (s, 2H), 3.03(s, 4H), 2.78 (s, 3H), 2.00 (d, J = 7.6 Hz, 2H), 1.24 (s, 9H), 1.08 (s,2H), 0.85 (s, 2H). 632 96% 4-55

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.72 (s, 1H), 10.04 (s, 1H),9.57 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 9.1 Hz, 1H), 7.03 (d, J= 9.6 Hz, 1H), 4.44 (s, 1H), 2.99 (s, 1H), 2.82 (s, 3H), 2.78 (s, 2H),2.54 (s, 2H), 1.26 (s, 2H), 1.08 (s, 2H). 491 91% 4-56

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.87 (s, 1H), 10.45 (s, 1H),8.93 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.23(s, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.68 (s, 1H), 4.42 (s, 1H), 2.78 (s,3H), 2.68 (s, 3H), 1.26 (s, 2H), 1.08 (s, 2H). 490 96% 4-57

¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 11.75 (s, 1H), 9.64 (s, 1H, 8.92(s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.63 (d,J = 7.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 4.48 (s, 2H), 4.40 (s, 1H),2.72 (d, J = 27.2 Hz, 7H), 2.62 (s, 3H), 1.25 (s, 2H), 1.08 (s, 2H).M-(Me)₂N 389 100% 4-58

¹H NMR (400 MHz, DMSO) δ 14.79 (s, 1H), 9.84 (s, 1H), 8.92 (s, 1H), 7.97(d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.62 (s, 1H), 7.56 (s,1H), 7.20 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 4.64 (s, 2H), 4.39 (s, 1H),3.57 (s, 2H), 2.88 (s, 6H), 2.65 (d, J = 22.8 Hz, 3H), 1.24 (s, 1H),1.08 (s, 2H). 448 100% 4-59

¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 11.62 (s, 1H), 9.68 (s, 1H),8.92 (s, 1H), 7.9 (s, 1H), 6.95 (s, 2H), 6.77 (s, 1H), 6.46 (s, 1H),4.43 (s, 1H), 2.80 (s, 3H), 1.27 (s, 2H), 1.07 (s, 4H). 393 99% 4-60

¹H NMR (400 MHz, DMSO) δ 14.77 (s, 1H), 11.29 (s, 1H), 8.91 (s, 1H),7.97 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 6.97 (s, 1H), 6.61 (s, 1H), 4.42(s, 1H), 3.80 (d, J = 13.7 Hz, 7H), 2.78 (s, 3H), 1.26 (s, 2H), 1.06 (s,2H). 437 99% 4-61

¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 11.29 (s, 1H), 8.91 (s, 1H),8.81 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.93(s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 4.41 (s, 2H), 2.77 (s,3H), 1.25 (s, 2H), 1.06 (s, 2H). 393 98% 4-62

¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 11.50 (s, 1H), 9.79 (s, 1H),8.91 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 6.7 Hz, 1H), 6.86(s, 1H), 6.60 (s, 2H), 4.41 (s, 1H), 2.76 (s, 3H), 1.23 (s, 2H), 1.08(s, 2H). 393 100% 4-63

¹H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 10.24 (s, 1H), 8.93 (s, 1H),8.04 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 7.0 Hz,1H), 7.46 (d, J = 7.3 Hz, 2H), 7.35 (s, 1H), 4.43 (s, 1H), 2.77 (s, 3H),1.27 (s, 2H), 1.09 (s, 2H). 405 85% 4-64

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 13.88 (s, 1H), 8.94 (s, 1H),8.10 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 14.5, 7.6 Hz, 2H), 7.62 (s, 1H),4.44 (s, 1H), 2.71 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 447 89% 4-65

¹H NMR (400 MHz, DMSO) δ 14.44 (s, 1H), 11.53 (s, 1H), 8.84 (s, 1H),8.16 (d, J = 9.1 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 9.7 Hz,1H), 7.58 (t, J = 10.6 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.16 (t, J =7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.62 (s, 1H), 5.77 (s, 1H), 1.77(d, J = 17.9 Hz, 3H). 449 94.06% 4-66

¹H NMR (400 MHz, DMSO) δ 14.79 (s, 1H), 11.42 (s, 1H), 8.70 (s, 1H),8.04 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.0 Hz,1H), 7.25 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H),6.61 (s, 1H), 4.23 (s, 1H), 2.70 (s, 3H), 1.06 (s, 2H), 0.81 (s, 2H).359 91.2% 4-67

¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.71 (s, 1H), 8.16 (d, J = 4.8Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 5.94 (dd, J = 3.4, 1.8Hz, 1H), 5.10 (s, 1H), 4.22-4.08 (m, 1H), 2.33 (s, 3H), 1.09-0.88 (m,4H). 378 97% 4-68

¹H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 8.92 (s, 1H), 8.35 (d, J = 4.4Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 7.8 Hz,1H), 7.21 (dd, J = 7.7, 4.0 Hz, 1H), 4.47-4.34 (m, 2H), 2.69 (s, 3H),1.28 (d, J = 6.6 Hz, 2H), 1.10 (s, 2H). 378 98% 4-69

¹H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.39 (t, J = 3.1 Hz, 1H), 8.08(t, J = 9.0 Hz, 2H), 7.22 (dd, J = 8.1, 4.1 Hz, 1H), 6.74 (d, J = 2.9Hz, 1H), 4.48-4.36 (m, 1H), 2.67 (s, 3H), 1.26 (d, J = 7.0 Hz, 4H), 1.09(s, 4H). 392 98% 4-70

¹H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.39 (t, J = 3.1 Hz, 1H), 8.07(t, J = 9.0 Hz, 1H), 7.21 (dt, J = 7.7, 3.7 Hz, 1H), 6.74 (d, J = 2.9Hz, 1H), 4.50-4.32 (m, 1H), 2.67 (s, 3H), 1.33-1.19 (d, J = 7.0 Hz, 2H),1.09 (s, 2H). 392 96% 4-71

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.96 (s, 1H), 8.92(s, 1H), 8.24(s, 1H), 8.06 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.61 (t, J = 2.8 Hz,1H), 6.57 (s, 1H), 4.59- 4.15 (dm, 1H), 2.64 (s, 3H), 1.26 (d, J = 6.8Hz, 2H), 1.09 (m, 2H). 378 98% 4-72

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 13.15 (s, 1H), 8.93 (s, 1H),8.27 (d, J = 6.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.9 Hz,1H), 7.19 (t, J = 7.1 Hz, 1H), 6.88 (s, 1H), 4.49-4.33 (m, 1H), 2.77 (s,3H), 1.39-1.21 (d, J = 7.0 Hz, 2H), 1.15-1.01 (m, 2H). 394 98% 4-73

¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 12.94 (s, 1H), 8.93 (s, 1H),8.72 (s, 1H), 8.65 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 6.93 (s, 1H),4.53-4.29 (m, 1H), 2.77 (s, 3H), 1.32-1.19 (m, 3H), 1.17-0.95 (m, 2H).403 92% 4-74

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 13.00 (s, 1H), 8.94 (s, 1H),8.53 (s, 7H), 8.04 (d, J = 8 Hz, 1H), 7.69 (dd, J = 4.4, 2.4 Hz, 1H),7.01 (s, 6H), 4.58-4.31 (m, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.6 Hz,15H), 1.18- 1.01 (m, 16H). 403 92% 4-75

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 13.95 (s, 1H), 8.94 (s, 1H),8.58 (s, 2H), 8.09 (d, J = 8.7 Hz, 1H), 7.60-7.51 (m, 1H), 4.53-4.33 (m,1H), 2.73 (s, 3H), 1.35-1.17 (m, 2H), 1.15-1.01 (m, 2H) 423 86% 4-76

¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.99 (s, 1H), 8.36 (d, J = 5.9Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.52 (d, J = 8.0 Hz,1H), 7.28 (t, J = 6.8 Hz, 1H), 4.54-4.44 (m, 1H), 2.76 (s, 3H), 1.34 (d,J = 6.8 Hz, 2H), 1.26-1.06 (m, 2H). 394 98% 4-77

¹H NMR (400 MHz, DMSO) δ 12.56 (s, 1H), 8.93 (s, 1H), 8.38 (t, J = 3.6Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.26 (dd, J= 8.0, 4.1 Hz, 1H), 6.83 (s, 1H), 4.57-4.33 (m, 1H), 2.78 (s, 3H),1.35-1.19 (d, J = 6.9 Hz, 2H), 1.15-1.01 (s, 2H). 378 98% 4-78

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 12.47 (s, 1H), 11.98 (s, 1H),8.91(s, 1H), 7.95 (m, 2H), 6.76 (s, 1H), 4.51-4.36 (m, 1H), 2.78 (s,3H), 1.26 (d, J = 6.9 Hz, 2H), 1.17-1.01 (m, 2H). 395 95% 4-79

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 13.19 (d, J = 6.5 Hz, 1H), 9.29(d, J = 2.9 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H), 6.94 (s, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.06 (s, 1H), 4.49-4.35 (m, 1H), 2.77 (s, 3H), 1.26 (d, J= 7.2 Hz, 2H), 1.13-0.99 (s, 2H). 379 98% 4-80

¹H NMR (400 MHz, DMSO) δ 15.167 (s, 1H), 14.59 (s, 1H), 13.80 (s, 1H),9.32 (s, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 6.1 Hz, 1H), 8.25(d, J = 6.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 4.51-4.39(m, 1H), 2.76 (m, 3H), 1.29-1.17 (d, J = 7.0 Hz, 2H), 1.17-0.97 (m, 2H).378 85% 4-81

¹H NMR (400 MHz, DMSO) δ 14.56 (s, 1H), 13.05 (s, 1H), 8.95 (s, 1H),8.68 (s, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.62 (s, 1H), 7.12 (s, 1H),4.51-4.36 (m, 1H), 2.76 (s, 3H), 1.33-1.19 (d, J = 7.1 Hz, 2H),1.13-1.05 (s, 2H). 378 85% 4-82

¹H NMR (400 MHz, DMSO) δ 14.88 (s, 1H), 14.57 (s, 1H), 13.46 (s, 1H),9.41 (s, 1H), 8.96 (s, 1H), 8.52 (d, J = 6.5 Hz, 1H), 8.21-7.93 (m, 2H),7.38 (s, 1H), 4.53- 4.29 (m, 1H), 2.77 (s, 3H), 1.35-1.17 (d, J = 6.7Hz, 2H), 1.19-1.03 (s, 2H). 378 98% 4-83

421 90% 4-84

421 98% 4-85

482 93% 4-86

¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 10.06 (s, 1H), 8.81 (s, 1H),7.88 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.80(d, J = 8.1 Hz, 1H), 4.36 (m, 1H), 3.06 (s, 2H), 1.06 (m, 4H). 392 95%4-87

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 8.91 (s, 1H), 8.03 (d, J = 9.3Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.56-7.22(m, 3H), 4.57-4.32 (m, 1H), 2.84 (s, 3H), 1.27 (m, 2H), 1.06 (m, 2H).378 98% 4-88

¹H NMR (400 MHz, DMSO) δ 14.50 (s, 1H), 13.22 (s, 1H), 8.84 (s, 1H),8.10-7.80 (m, 2H), 7.74-7.58 (s, 1H), 7.49 (s, 1H), 4.38 (m, 1H), 2.78(s, 3H), 1.30-1.12 (m, 2H), 1.00 (m, 2H). 422 98% 4-89

¹H NMR (400 MHz, DMSO) δ 14.56 (s, 1H), 8.93 (s, 1H), 8.02 (d, J = 9.2Hz, 1H), 7.76 (dd, J = 8.8, 3.5 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.41(s, 1H), 7.28 (t, J = 9.3 Hz, 1H), 4.43 (m, 1H), 2.82 (s, 3H), 1.26 (d,J = 6.4 Hz, 3H), 1.05 (s, 2H). 396 98% 4-90

¹H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.76(s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.36 (s, 1H), 7.20 (t, J = 9.0 Hz,1H), 4.35 (m, 1H), 2.76 (s, 3H), 1.30-1.09 (m, 3H), 0.96 (s, 2H). 39698% 4-91

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 8.86 (s, 1H), 7.96 (m, 3H), 7.59(s, 1H), 7.41 (d, J = 5.1 Hz, 2H), 4.35 (m, 1H), 2.72 (s, 3H), 1.17 (m,2H), 1.00 (m, 2H). 394 96% 4-92

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.86 (s, 1H), 8.08 (d, J = 7.6Hz, 1H), 7.97 (m, 2H), 7.36 (m, 3H), 4.32 (m, 1H), 2.57 (s, 3H), 1.03(m, 4H). 394 98% 4-93

¹H NMR (400 MHz, DMSO) δ 14.51 (s, 1H), 8.92 (ss, 1H), 8.32 (d, J = 8.1Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.05 (t, J = 13.1 Hz, 1H), 7.90 (s,1H), 7.70 (t, J = 8.2 Hz, 1H), 4.45 (m, 1H), 2.86 (s, 3H), 1.26 (t, J =11.6 Hz, 2H), 1.10 (d, J = 21.6 Hz, 2H). 423 98% 4-94

¹H NMR (400 MHz, DMSO) δ 14.46 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 7.75(d, J = 9.2 Hz, 1H), 7.52 (dd, J = 8.8, 3.5 Hz, 1H), 7.20-7.11 (m, 3H),4.43 (s, 1H), 2.64 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.05 (s, 2H). 37898% 4-95

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.94 (s, 1H), 8.05 (d, J = 9.3Hz, 1H), 7.64 (d, J = 2.9 Hz, 1H), 7.54 (s, 1H), 7.36 (d, J = 6.6 Hz,2H), 4.44 (m, 1H), 2.85 (s, 3H), 1.34-1.19 (m, 2H), 1.06 (s, 2H). 39696% 4-96

¹H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.38 (s, 1H), 8.04 (d, J = 9.2Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.55 (s,1H), 4.44 (m, 1H), 2.83 (s, 3H), 1.35-1.18 (m, 2H), 1.06 (m, 2H). 40398% 4-97

¹H NMR (400 MHz, DMSO) δ 14.56 (s, 1H), 8.94 (s, 1H), 8.04 (d, J = 9.1Hz, 1H), 7.95-7.77 (m, 2H), 7.53-7.33 (m, 2H) 4.45 (m, 1H), 2.83 (s,3H), 1.27 (d, J = 6.3 Hz, 2H), 1.05 (s, 2H). 462 98% 4-98

¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H), 8.86 (s, 1H), 7.95 (d, J = 9.0Hz, 1H), 7.43 (s, 1H), 7.03 (t, J = 8.1 Hz, 1H), 6.77 (d, J = 7.4 Hz,1H), 6.39 (d, J = 7.1 Hz, 1H), 4.38 (m, 1H), 2.77 (s, 3H), 1.19 (m, 2H),0.98 (m, 1H). 393 96%

TABLE 5

Com- pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 5-1

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 10.91 (s, 1H),8.89 (s, 1H), 7.94 (d, J = 8.60 Hz, 1H), 7.13-6.90 (m, 3H), 4.67 (s,2H), 4.38 (s, 1H), 2.62 (s, 3H), 1.23 (d, J = 5.80 Hz, 2H), 1.04 (s,2H). 409 97% 5-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 10.78 (s, 1H),8.90 (s, 1H), 7.95 (d, J = 8.72 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J = 8.03Hz, 1H), 7.13 (d, J = 8.17 Hz, 1H), 4.38 (s, 1H), 3.57 (s, 2H), 2.62 (s,3H), 1.24 (d, J = 6.14 Hz, 2H), 1.05 (s, 2H). 425 98% 5-3

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 10.64 (s, 1H),8.98 (s, 1H), 8.05 (d, J = 8.72 Hz, 1H), 7.90 (s, 1H), 7.62 (s, 1H),4.92 (s, 2H), 4.46 (s, 1H), 2.71 (s, 3H), 1.30 (s, 3H), 1.15 (s, 2H).454 97% 5-4

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 11.39 (s, 1H),8.90 (s, 1H), 7.96 (d, J = 8.72 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H),4.75 (s, 2H), 4.39 (s, 1H), 2.62 (s, 3H), 1.23 (d, J = 5.26 Hz, 2H),1.06 (s, 2H). 434 98% 5-5

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 10.94 (s, 1H),8.80 (s, 1H), 7.90 (s, 1H), 7.11 (d, J = 26.18 Hz, 2H), 4.67 (s, 2H),1.15 (s, 4H). 425 98% 5-6

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 10.87 (s, 1H),6.90 (s, 1H), 7.96 (d, J = 8.58 Hz, 1H), 7.14 (d, J = 8.35 Hz, 1H), 6.97(d, J = 8.15 Hz, 1H), 6.89 (s, 1H), 4.69 (s, 2H), 4.39 (s, 1H), 2.62 (s,3H), 1.23 (s, 2H), 1.04 (s, 2H). 409 98% 5-9

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 10.28 (s, 1H),8.90 (s, 1H), 7.94 (d, J = 8.20 Hz, 1H), 7.23 (s, 1H), 7.17 (s, 1H),7.03 (s, 1H), 4.38 (s, 2H), 2.97 (s, 2H), 2.63 (s, 2H), 1.23 (s, 2H),1.04 (s, 2H). 407 85% 5-10

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.47 (s, 1H),11.39 (s, 1H), 8.91 (s, 1H), 7.98 (d, J = 8.50 Hz, 1H), 7.89 (s, 1H),7.70 (d, J = 8.10 Hz, 1H), 7.35 (d, J = 8.11 Hz, 1H), 4.40 (s, 1H), 3.49(d, J = 87.04 Hz, 2H), 2.62 (s, 3H), 1.23 (s, 2H), 1.08 (s, 3H). 422 98%5-11

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.96 (s, 1H),11.63 (s, 1H), 8.92 (s, 1H), 8.69 (s, 1H), 8.34 (s, 1H), 8.00 (d, J =8.65 Hz, 1H), 4.41 (s, 1H), 2.61 (d, J = 29.62 Hz, 3H), 1.24 (d, J =5.11 Hz, 2H), 1.09 (s, 2H). 423 99% 5-12

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 12.44-11.74 (m,2H), 8.91 (s, 1H), 7.98 (d, J = 8.01 Hz, 1H), 7.53-7.03 (m, 3H), 4.39(s, 1H), 2.61 (s, 3H), 1.20 (d, J = 26.27 Hz, 3H), 1.05 (s, 2H). 422 96%5-13

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83 (s, 1H), 8.88 (s, 1H),7.90 (s, 2H), 6.70 (s, 3H), 4.27 (d, J = 77.51 Hz, 4H), 2.60 (d, J =25.07 Hz, 3H), 1.23 (s, 2H), 1.02 (s, 2H). 395 98% 5-14

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 8.76 (s, 1H),7.83 (d, J = 9.18 Hz, 1H), 6.92-6.81 (m, 2H), 6.70 (d, J = 7.26 Hz, 1H),6.19 (d, J = 22.26 Hz, 1H), 4.16 (s, 4H), 3.39 (s, 3H), 2.50 (s, 7H).411 96% 5-15

8-N Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.61 (s, 1H),8.19 (d, J = 11.38 Hz, 1H), 7.55 (d, J = 8.31 Hz, 1H), 7.47 (s, 1H),6.68 (s, 1H), 6.54 (d, J = 8.26 Hz, 1H), 4.00 (s, 2H), 3.73 (s, 1H),1.15-0.91 (m, 5H). 382 94% 5-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.90 (s, 1H), 8.94 (s, 1H),7.94 (d, J = 9.06 Hz, 1H), 6.95 (d, J = 8.81 Hz, 2H), 6.63 (d, J = 7.73Hz, 1H), 6.14 (s, 1H), 4.43 (s, 1H), 3.31 (s, 2H), 2.79 (s, 2H), 2.70(s, 3H), 1.90 (s, 2H), 1.30 (s, 2H), 1.08 (s, 2H). 393 94% 5-17

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.89 (s, 1H),8.60 (s, 1H), 7.94 (d, J = 8.81 Hz, 1H), 7.67 (s, 1H), 7.10 (s, 1H),4.38 (s, 1H), 4.27 (s, 2H), 3.63 (s, 2H), 2.66 (s, 3H), 1.24 (d, J =5.67 Hz, 2H), 1.07 (s, 2H). 440 97% 5-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 8.89 (s, 1H),7.91 (d, J = 8.74 Hz, 1H), 6.33 (s, 1H), 6.24 (s, 1H), 4.57 (s, 2H),4.38 (s, 2H), 2.64 (s, 3H), 1.23 (d, J = 5.42 Hz, 3H), 1.03 (s, 2H). 42497% 5-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.91 (s, 1H), 6.29(s, 1H), 6.18 (s, 1H), 4.37 (s, 2H), 4.18 (s, 3H), 3.10 (s, 2H), 2.65(d, J = 16.81 Hz, 6H), 1.23 (s, 3H), 1.03 (s, 2H). 424 97% 5-20

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.01 (d, J = 9.26Hz, 1H), 7.85-7.65 (m, 2H), 7.64-7.40 (m, 1H), 7.36 (s, 1H), 4.46 (s,1H), 4.32 (s, 3H), 3.63 (s, 3H), 2.74 (s, 3H), 1.30 (d, J = 5.75 Hz,2H), 1.11 (s, 2H). 396 98% 5-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.85 (d, J =23.76 Hz, 1H), 7.87 (t, J = 19.93 Hz, 1H), 7.17 (s, 1H), 6.99 (d, J =9.29 Hz, 2H), 4.37 (s, 1H), 4.20 (s, 2H), 3.59 (s, 1H), 3.44 (s, 2H),2.53 (s, 3H), 1.24 (s, 2H), 1.07 (d, J = 23.80 Hz, 2H). 420 95% 5-22

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.78 (s, 1H),7.87 (d, J = 9.24 Hz, 1H), 7.26 (d, J = 10.63 Hz, 1H), 7.11 (s, 1H),7.04 (s, 1H), 4.20 (s, 3H), 2.00 (dd, J = 7.56, 15.22 Hz, 1H), 1.21 (d,J = 14.05 Hz, 4H). 436 98% 5-24

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.87 (d, J = 9.25Hz, 1H), 7.75 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 4.17 (s, 3H), 3.47(s, 3H), 1.32- 1.05 (m, 8H). 412 96% 5-25

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 10.92 (s, 1H),10.86 (s, 1H), 8.96 (s, 1H), 7.98 (t, J = 12.31 Hz, 1H), 7.15 (d, J =7.60 Hz, 1H), 7.00 (d, J = 8.89 Hz, 2H), 4.44 (s, 1H), 2.67 (s, 3H),1.28 (s, 2H), 1.12 (s, 2H). 394 98% 5-26

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 10.94 (s, 1H),10.87 (s, 1H), 8.86 (s, 1H), 7.97 (d, J = 8.82 Hz, 1H), 7.17 (d, J =7.41 Hz, 3H), 4.29 (s, 1H), 1.23 (s, 4H). 410 98% 5-27

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 7.96 (d, J = 8.75Hz, 1H), 6.96 (d, J = 10.17 Hz, 1H), 6.92 (d, J = 8.04 Hz, 1H), 6.72 (d,J = 7.83 Hz, 1H), 4.44 (s, 1H), 3.63 (s, 2H), 3.09 (s, 2H), 2.70 (s,3H), 1.30 (d, J = 5.29 Hz, 2H), 1.10 (s, 2H). 411 98% 5-28

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.89 (s, 1H),7.94 (d, J = 8.48 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.33 (d, J = 8.57Hz, 1H), 6.94 (d, J = 8.45 Hz, 1H), 4.39 (s, 1H), 3.80 (s, 2H), 3.48 (s,2H), 2.64 (s, 3H), 1.23 (s, 2H), 1.06 (s, 2H). 443 98% 5-29

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 10.84 (s, 1H),8.83 (s, 1H), 7.86 (d, J = 8.65 Hz, 1H), 6.52 (s, 2H), 4.38 (s, 2H),4.31 (s, 1H), 3.89 (s, 2H), 2.54 (s, 3H), 1.16 (s, 2H), 1.00 (s, 2H).436 98% 5-30

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 10.91 (s, 1H),8.79 (s, 1H), 7.88 (d, J = 9.15 Hz, 1H), 6.75 (d, J = 14.51 Hz, 2H),4.45 (t, J = 4.51 Hz, 2H), 4.27-4.16 (m, 1H), 3.96 (t, J = 4.53 Hz, 2H),1.17 (d, J = 7.20 Hz, 4H). 452 99% 5-31

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.95 (d, J = 8.62Hz, 1H), 6.79 (dd, J = 7.23, 14.68 Hz, 3H), 4.43 (s, 1H), 4.23 (d, J =10.57 Hz, 1H), 4.06 (d, J = 10.42 Hz, 1H), 3.60-3.41 (m, 3H), 2.70 (s,3H), 1.30 (d, J = 5.98 Hz, 2H), 1.09 (s, 2H). 425 99% 5-32

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 7.98 (d, J = 8.04Hz, 1H), 7.09 (s, 1H), 6.96 (s, 2H), 4.44 (s, 1H), 4.15 (s, 2H), 3.29(s, 3H), 2.69 (s, 3H), 2.02 (s, 2H), 1.30 (s, 2H), 1.10 (s, 2H). 409 99%5-33

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 7.77 (d, J = 6.81Hz, 1H), 6.59 (s, 3H), 4.25 (s, 1H), 4.04 (s, 2H), 3.27 (d, J = 11.94Hz, 1H), 2.96-2.79 (m, 1H), 2.52 (s, 3H), 1.18 (t, J = 8.54 Hz, 3H),1.12 (d, J = 5.48 Hz, 2H), 0.91 (s, 2H). 409 98% 5-34

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.72 (d, J = 8.62Hz, 1H), 6.54 (s, 3H), 4.20 (s, 2H), 4.03 (d, J = 10.38 Hz, 2H), 3.52(t, J = 8.97 Hz, 1H), 3.31 (s, 1H), 2.46 (s, 3H), 1.07 (d, J = 5.70 Hz,2H), 0.96 (d, J = 4.88 Hz, 3H), 0.86 (s, 2H). 409 98% 5-35

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.89 (s, 1H),7.93 (d, J = 8.73 Hz, 1H), 7.48 (d, J = 52.24 Hz, 1H), 6.96 (d, J = 7.83Hz, 1H), 6.80 (s, 1H), 6.74 (d, J = 7.83 Hz, 1H), 4.38 (s, 1H), 3.76 (d,J = 12.76 Hz, 1H), 2.63 (s, 3H), 2.07 (s, 1H), 1.85 (s, 1H), 1.66 (s,1H), 1.58- 1.37 (m, 3H), 1.23 (d, J = 6.52 Hz, 2H), 1.06 (s, 2H). 46298% 5-36

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 10.70 (s, 1H),8.92 (s, 1H), 8.09 (d, J = 8.43 Hz, 1H), 7.82 (s, 1H), 7.04 (d, J =22.18 Hz, 1H), 6.64 (d, J = 10.90 Hz, 2H), 4.52-4.28 (m, 3H), 4.01-3.82(m, 2H), 1.20 (t, J = 10.03 Hz, 2H), 1.12 (d, J = 3.28 Hz, 2H). 456 97%5-37

8-Me

¹H NMR (400 MHz, DMSO) δ 8.85 (d, J = 3.12 Hz, 1H), 7.90 (d, J = 8.88Hz, 1H), 6.71 (d, J = 5.48 Hz, 3H), 5.23 (d, J = 3.10 Hz, 1H), 5.07 (d,J = 2.78 Hz, 1H), 4.42-4.27 (m, 1H), 4.22-4.12 (m, 2H), 2.55 (s, 3H),1.74 (ddd, J = 8.97, 14.93, 17.91 Hz, 1H), 1.62-1.45 (m, 1H). 413 98%5-38

8-Me

¹H NMR (400 MHz, DMSO) δ 14.44 (d, J = 137.56 Hz, 2H), 10.82 (d, J =68.59 Hz, 1H), 8.85 (t, J = 9.38 Hz, 1H), 7.93 (t, J = 10.51 Hz, 1H),6.56 (t, J = 40.40 Hz, 2H), 4.44 (d, J = 4.54 Hz, 3H), 4.39-4.29 (m,1H), 4.04-3.90 (m, 3H), 2.54 (s, 3H), 1.64 (m, 2H). 454 98% 5-39

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.10 (d, J = 8.56Hz, 1H), 7.69 (s, 1H), 7.18 (s, 1H), 4.41 (s, 2H), 4.23-4.19 (m, 3H),3.51 (s, 2H), 1.22 (d, J = 6.34 Hz, 2H), 1.11 (s, 2H). 416 98% 5-40

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.91 (s, 1H),7.97 (d, J = 8.68 Hz, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 4.68 (d, J = 4.53Hz, 2H), 4.58 (d, J = 4.64 Hz, 2H), 4.40 (dd, J = 3.32, 6.77 Hz, 1H),2.61 (s, 3H), 1.24 (d, J = 6.14 Hz, 2H), 1.10 (s, 2H). 434 98% 5-41

8-OMe

¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 10.91 (s, 1H), 8.62 (s, 1H),7.89 (d, J = 9.04 Hz, 1H), 6.74 (d, J = 14.28 Hz, 2H), 5.08 (d, J =64.31 Hz, 1H), 4.45 (s, 2H), 4.19 (s, 1H), 3.96 (s, 2H), 1.80 (d, J =26.47 Hz, 1H), 1.65 (dd, J = 7.14, 16.55 Hz, 1H). 470 98% 5-42

8-OMe

¹H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.86 (d, J = 9.34 Hz, 1H), 6.87(d, J = 8.16 Hz, 1H), 6.84 (s, 1H), 6.70 (d, J = 8.14 Hz, 1H), 5.18-4.96 (m, 1H), 4.17 (s, 3H), 3.36 (s, 2H), 1.84-1.58 (m, 2H). 429 98%5-43

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75- 14.70 (s, 1H), 8.80-8.76(s, 1H), 7.89- 7.83 (d, J = 9.4 Hz, 1H), 6.92-6.86 (d, J = 11.4 Hz, 1H),6.77-6.73 (s, 1H), 6.16-6.10 (s, 1H), 4.27-4.15 (s, 3H), 3.47-3.41 (s,3H), 3.40-3.34 (q, J = 3.6 Hz, 2H), 1.20-1.09 (dd, J = 14.4, 5.5 Hz,4H). 429 90% 5-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.77- 14.65 (s, 1H), 8.80-8.76(s, 1H), 7.89- 7.83 (d, J = 9.3 Hz, 1H), 7.09-7.03 (t, J = 1.6 Hz, 1H),6.90-6.84 (t, J = 1.6 Hz, 1H), 6.19-6.10 (s, 1H), 4.26-4.15 (m, 3H),3.48-3.39 (s, 5H), 1.20-1.09 (ddd, J = 10.6, 5.5, 3.0 Hz, 4H). 445 100%5-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.80- 8.74 (s, 1H), 7.68-7.80(d, J = 9.3 Hz, 1H), 6.81-6.71 (dd, J = 17.1, 2.1 Hz, 2H), 4.28-4.18(tt, J = 7.2, 4.3 Hz, 1H), 4.18-4.12 (t, J = 4.2 Hz, 2H), 3.44-3.35 (m,5H), 2.16-2.10 (s, 3H), 1.20-1.08 (m, 4H). 425 100% 5-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.79- 8.75 (s, 1H), 7.87-7.81(d, J = 9.3 Hz, 1H), 6.55-6.49 (s, 1H), 6.43-6.39 (s, 1H), 4.27-4.18 (s,1H), 4.16-4.10 (t, J = 4.3 Hz, 2H), 3.33-3.5 (s, 2H), 2.57-2.52 (s, 3H),1.20-1.09 (m, 4H). 426 96% 5-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83- 14.56 (s, 1H), 8.81-8.77(s, 1H), 8.66- 8.59 (m, 1H), 7.95-7.89 (d, J = 9.3 Hz, 1H), 7.89-7.84(t, J = 1.7 Hz, 1H), 7.24- 7.19 (s, 1H), 4.30-4.18 (m, 3H), 3.67- 3.60(q, J = 3.8 Hz, 2H), 3.52-3.44 (s, 3H), 1.20-1.12 (td, J = 6.5, 5.8, 2.7Hz, 4H). 456 100% 5-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.22- 14.17 (m, 1H), 8.97-8.90(s, 1H), 8.84- 8.80 (s, 1H), 7.97-7.90 (d, J = 9.0 Hz, 1H), 7.51-7.47(s, 1H), 7.07-7.02 (s, 1H), 4.69-4.57 (s, 4H), 4.28-4.18 (p, J = 5.7 Hz,1H), 3.42-3.35 (s, 3H), 1.21-1.12 (d, J = 5.6 Hz, 4H). 436 100% 5-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70- 14.66 (s, 1H), 8.84-8.80(s, 1H), 7.97- 7.92 (d, J = 9.0 Hz, 1H), 7.78-7.74 (s, 1H), 7.08-7.04(s, 1H), 5.00-4.94 (t, J = 4.9 Hz, 2H), 4.82-4.74 (t, J = 4.8 Hz, 2H),4.27-4.18 (p, J = 5.7 Hz, 1H), 3.43-3.38 (s, 3H), 1.21-1.13 (d, J = 5.6Hz, 4H). 437 85% 5-50

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.94 (s, 1H),7.87 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 11.4 Hz, 1H), 6.75 (s, 1H), 6.13(s, 1H), 4.21 (m, 3H), 3.40 (s, 3H), 1.31-0.94 (m, 4H). 429 90% 5-51

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.88 (s, 1H),7.91 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 6.72 (s, 1H), 6.07 (s, 1H).4.48-4.30 (m, 1H), 4.20 (m, 2H), 3.43 (m, 2H), 2.70-2.56 (m, 3H), 1.24(d, J = 4.0 Hz, 2H), 1.04 (s, 2H). 429 98% 5-52

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.5 (b, 1H), 8.91 (s, 1H), 8.86(s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 6.90 (s, 1H), 4.63 (s,4H), 4.39 (mz, 1H), 2.61 (s, 3H), 1.24 (d, J = 4.6 Hz, 2H), 1.09 (s,2H). 420 98% 5-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.88 (s, 1H),7.90 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 6.76 (s, 1H), 4.44- 4.28 (m,1H), 4.15 (m, 2H), 3.43 (m, 2H), 2.65 (s, 3H), 1.24 (s, 2H), 1.04 (s,2H). 521 97% 5-54

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.89 (s, 1H),7.91 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 11.3 Hz, 1H), 6.59 (s, 1H), 4.37(m, 1H), 4.22 (s, 2H), 3.39 (s, 2H), 2.65 (s, 3H), 1.22 (m, 2H), 1.00(m, 2H). 413 97% 5-55

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.05 (d, J = 8.6Hz, 1H), 6.91- 6.49 (m, 3H), 4.46-4.36 (m, 1H), 4.16 (m, 2H), 3.49 (m,2H), 2.67 (s, 3H), 1.19 (t, J = 15.1 Hz, 2H), 1.09 (s, 2H). 415 98% 5-56

¹H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.15 (d, J = 7.00 Hz, 1H),7.24-7.02 (m, 2H), 6.78 (d, J = 8.23 Hz, 1H), 4.28-4.13 (m, 2H), 4.05-3.86 (m, 1H), 3.49-3.34 (m, 2H), 2.90 (d, J = 2.66 Hz, 3H), 1.44-1.32(m, 2H), 1.28-1.17 (m, 2H). 395 98% 5-57

¹H NMR (400 MHz, DMSO) δ 15.13 (s, 1H), 8.84 (s, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.71 (s, 1H), 7.20-7.06 (m, 2H), 6.73 (t, J = 16.6 Hz, 1H),4.30 (m, 1H), 4.22-4.17 (m, 2H), 3.68 (s, 2H), 3.44 (s, 3H), 1.43-0.95(m, 4H). 393 98%

TABLE 6

Com- pound MS No. R³ = R² = NMR (MH⁺) HPLC 6-1

Me ¹H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.35 (m, 2H), 6.96 (s, 1H),6.80 (m, 2H), 4.30-4.19 (m, 1H), 3.75 (s, 3H), 2.59 (s, 3H), 0.96 (m,2H), 0.79 (m, 2H). 368 98% 6-2

Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.89 (s, 1H), 7.92 (d, J =8.6 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.24 (dd, J = 15.3, 7.9 Hz, 2H),7.14 (d, J = 7.4 Hz, 1H), 4.38 (m, 1H), 3.76 (s, 3H), 2.55 (s, 3H),1.41- 1.15 (m, 2H), 1.12-0.96 (m, 2H). 482 90% 6-3

Me ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 8.95 (s, 1H), 8.00 (d, J =8.8 Hz, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.3 Hz, 2H),7.45-7.36 (m, 3H), 7.26 (d, J = 8.6 Hz, 2H), 5.25 (s, 2H), 4.54-4.32 (m,1H), 2.67 (s, 3H), 1.30 (d, J = 6.2 Hz, 2H), 1.11 (s, 2H). 444 99% 6-4

Me ¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 8.90 (s, 1H), 7.94 (d, J =8.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.33(s, 1H), 3.84 (s, 3H), 2.61 (s, 3H), 1.23 (d, J = 6.2 Hz, 2H), 1.05 (s,2H). 368 96% 6-5

Me ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 8.88 (s, 1H), 7.92 (d, J =8.9 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 4.71(dt, J = 12.0, 6.0 Hz, 1H), 4.38 (m, 1H), 2.58 (d, J = 26.0 Hz, 3H),1.32 (d, J = 6.0 Hz, 6H), 1.23 (q, J = 6.9 Hz, 2H), 1.02 (s, 2H). 39699% 6-6

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.91 (s, 1H), 7.98 (d, J =8.8 Hz, 1H), 7.58 (s, 4H), 4.52- 4.24 (m, 1H), 2.60 (s, 3H), 1.23 (q, J= 7.0 Hz, 2H), 1.15-1.01 (m, 2H). 422 99% 6-7

Me ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.91 (s, 1H), 7.99 (d, J =8.8 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H),7.52-7.44 (m, 2H), 4.52-4.20 (m, 1H), 2.80 (s, 3H), 1.23 (d, J = 6.8 Hz,2H), 1.08 (s, 2H). 422 99% 6-8

Me ¹H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 8.76 (s, 1H), 7.86 (d, J =8.7 Hz, 1H), 7.60-7.52 (m, 1H), 7.45 (ddd, J = 10.9, 9.8, 4.6 Hz, 3H),4.25 (dt, J = 10.7, 3.6 Hz, 1H), 2.43 (s, 3H), 1.06 (dq, J = 9.4, 7.1Hz, 2H), 0.99-0.71 (m, 3H). 422 99% 6-9

Me ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 8.83 (s, 1H), 7.87 (d, J =8.7 Hz, 1H), 6.61 (s, 2H), 4.33 (m, 1H), 3.74 (s, 6H), 3.68 (s, 3H),2.57 (s, 3H), 1.18 (d, J = 6.4 Hz, 2H), 1.01 (s, 2H). 428 95% 6-10

Me ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 8.88 (s, 1H), 7.90 (d, J =8.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.70(dd, J = 8.4, 2.3 Hz, 1H), 4.47-4.28 (m, 1H), 3.85 (s, 3H), 3.75 (s,3H), 2.55 (s, 3H), 1.21 (dd, J = 6.7, 4.5 Hz, 2H), 1.02 (dd, J = 10.3,4.5 Hz, 2H). 398 96% 6-11

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.80 (s, 1H), 7.86 (d, J =8.1 Hz, 1H), 7.32 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 4.25 (s, 1H), 3.92(s, 3H), 2.57 (s, 3H), 1.41-1.10 (m, 2H), 0.89 (m, 2H). 386 96% 6-12

Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.90 (s, 1H), 7.93 (d, J =8.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.97 (s, 1H), 6.93 (dd, J = 8.2,1.7 Hz, 1H), 4.39 (tt, J = 7.1, 3.8 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H),2.63 (s, 3H), 1.24 (d, J = 6.8 Hz, 2H), 1.07 (s, 2H). 398 99% 6-13

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.90 (s, 1H), 7.94 (d, J =8.7 Hz, 1H), 7.54 (s, 1H), 7.35 (dd, J = 18.3, 8.3 Hz, 2H), 4.39 (m,1H), 3.95 (s, 3H), 2.62 (s, 3H), 1.23 (d, J = 5.8 Hz, 2H), 1.06 (s, 2H).402 99% 6-14

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.91 (s, 1H), 7.97 (d, J =8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.6Hz, 1H), 4.40 (m, 1H), 3.99 (s, 3H), 2.61 (s, 3H), 1.24 (d, J = 5.6 Hz,2H), 1.08 (s, 2H). 436 99% 6-15

Me ¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 8.89 (s, 1H), 7.93 (d, J =8.5 Hz, 1H), 7.20 (d, J = 12.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 4.38(m, 1H), 3.87 (s, 3H), 2.64 (s, 3H), 2.23 (s, 3H), 1.23 (m, 2H), 1.07(m, 2H). 362 99% 6-16

Me ¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 8.88 (s, 1H), 7.91 (d, J =8.6 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.62 (s, 1H), 6.52 (d, J = 6.8Hz, 1H), 4.94 (s, 2H), 4.39 (s, 1H), 3.84 (s, 3H), 2.63 (s, 3H), 1.23(s, 2H), 1.03 (s, 2H). 383 95% 6-17

Me ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.16 (s, 1H), 8.91 (s, 1H),7.96 (d, J = 8.9 Hz, 2H), 7.26 (dd, J = 28.6, 8.1 Hz, 2H), 4.39 (m, 1H),4.24 (m, 2H), 3.86 (m, 4H), 3.33 (m, 4H), 2.63 (s, 3H), 1.22 (d, J = 6.1Hz, 2H), 1.05 (s, 2H). 510 90% 6-18

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 9.12 (s, 1H), 8.90 (s, 1H),7.95 (d, J = 9.0 Hz, 1H), 7.29 (s, 1H), 7.26 (s, 2H), 4.39 (m, 1H), 3.92(s, 3H), 3.01 (s, 3H), 2.62 (s, 3H), 1.35-1.15 (m, 2H), 1.06 (m, 2H).461 98% 6-19

Me ¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 8.89 (s, 1H), 8.14 (d, J =14.8 Hz, 2H), 7.94 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.90(d, J = 7.9 Hz, 1H), 6.28 (s, 2H), 4.39 (s, 1H), 3.93 (s, 3H), 2.65 (s,3H), 1.19 (m, 2H), 1.04 (m, 2H). 426 98% 6-20

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.91 (s, 1H), 7.97 (d, J =8.7 Hz, 1H), 7.56 (d, J = 6.9 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 4.39(m, 1H), 3.91 (s, 3H), 2.62 (s, 3H), 1.52 (s, 9H), 1.24 (m, 2H), 1.07(m, 2H). 468 98% 6-21

Me ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 12.93 (s, 1H), 8.97 (s, 1H),8.02 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.38(d, J = 0.8 Hz, 1H), 4.39 (m, 1H), 3.67 (s, 3H), 2.62 (s, 3H), 1.52 (s,9H), 1.30 (m, 2H), 1.13 (m, 2H). 412 98% 6-22

Me ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.92 (s, 1H), 8.52 (s, 1H),7.97 (d, J = 8.3 Hz, 1H), 7.81 (s, 3H), 7.57 (d, J = 7.9 Hz, 1H), 7.36(d, J = 8.4 Hz, 1H), 4.39 (s, 1H), 3.96 (d, J = 24.7 Hz, 3H), 3.54 (s,2H), 2.99 (s, 2H), 2.69-2.54 (m, 3H), 1.23 (d, J = 454 95% 5.3 Hz, 2H),1.07 (s, 2H). 6-24

Me ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 9.40 (s, 1H), 8.92 (s, 1H),8.60 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H),4.40 (s, 1H), 4.00 (s, 3H), 3.66 (s, 2H), 3.28 (s, 2H), 2.85 (s, 6H),2.61 (s, 3H), 1.24 (s, 2H), 1.07 (s, 2H). 462 99% 6-25

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H),7.96 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.33(d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 4.40 (s, 1H), 3.98 (s, 3H), 3.33 (d,J = 5.1 Hz, 2H), 3.13 (d, J = 5.4 Hz, 554 95% 2H), 2.61 (s, 3H), 1.36(s, 9H), 1.24 (d, J = 4.4 Hz, 2H), 1.07 (s, 2H). 6-26

Me ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 10.43 (s, 1H), 8.91 (s, 1H),7.97 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.45(d, J = 8.6 Hz, 1H), 4.39 (m, 1H), 4.02 (s, 3H), 2.61 (s, 3H), 1.23 (m,2H), 1.07 (m, 2H). 396 98% 6-27

Me ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.91 (s, 1H), 8.47 (s, 1H),7.97 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.44 (d, J = 8.7Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 4.40 (m, 1H), 4.05 (s, 3H), 2.65 (s,3H), 1.25 (d, J = 6.7 Hz, 2H), 1.08 (s, 2H). 435 90% 6-28

Me ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.90 (s, 1H), 7.96 (d, J =8.4 Hz, 1H), 7.40 (d, J = 11.8 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 4.39(s, 1H), 3.94 (s, 5H), 2.62 (s, 3H), 1.23 (s, 2H), 1.06 (s, 2H). 407 95%6-29

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 10.43 (s, 1H), 8.91 (s, 1H),7.97 (d, J = 8.8 Hz, 1H), 7.86- 7.62 (m, 2H), 7.44 (d, J = 8.5 Hz, 1H),4.39 (s, 1H), 4.02 (s, 2H), 2.64 (s, 3H), 1.23 (s, 2H), 1.07 (s, 2H).396 95% 6-30

Me ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 2H), 8.93 (s, 1H), 8.33 (s, 1H),8.02 (d, J = 8.6 Hz, 1H), 7.80 (s, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.56(d, J = 8.4 Hz, 1H), 7.46 (s, 2H), 4.42 (s, 1H), 4.17 (s, 3H), 2.66 (s,3H), 1.35-1.15 (m, 2H), 1.09 (s, 2H). 484 85% 6-31

Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 11.37 (s, 1H), 8.90 (s, 1H),8.35 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J = 8.1Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.39 (s, 1H), 3.92 (s, 3H), 2.63 (s,3H), 1.23 (d, J = 5.2 Hz, 2H), 1.06 (s, 2H). 411 95% 6-32

Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.91 (s, 1H), 7.97 (d, J =8.7 Hz, 1H), 7.76 (s, 2H), 7.70 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.33(d, J = 8.4 Hz, 1H), 4.40 (s, 1H), 3.98 (s, 3H), 2.61 (s, 3H), 1.23 (s,2H), 1.07 (s, 2H). 411 94% 6-33

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.92 (s, 1H), 7.96 (d, J =8.6 Hz, 1H), 7.37 (s, 2H), 7.23 (d, J = 7.3 Hz, 1H), 4.39 (m, 1H), 3.89(s, 3H), 3.74 (m, 4H), 3.07 (s, 4H), 2.76 (s, 3H), 2.62 (s, 3H), 1.24(s, 2H), 1.06 (s, 2H). 480 96% 6-34

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.92 (s, 1H), 8.87 (s, 1H),7.97 (d, J = 8.1 Hz, 1H), 7.48 (s, 2H), 7.29 (d, J = 8.7 Hz, 1H), 4.40(m, 1H), 4.18 (s, 2H), 3.94 (s, 3H), 2.63 (s, 3H), 2.55 (s, 3H), 1.24(s, 2H), 1.05 (s, 2H). 411 86% 6-35

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.91 (s, 1H), 7.97 (d, J =8.6 Hz, 1H), 7.91 (s, 1H), 7.75 (d, J = 6.1 Hz, 1H), 7.44 (d, J = 8.1Hz, 1H), 4.39 (s, 1H), 4.02 (s, 3H), 2.61 (s, 3H), 1.23 (s, 2H), 1.07(s, 2H). 393 95% 6-36

Me ¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 8.90 (s, 1H), 7.95 (d, J =8.7 Hz, 1H), 7.37 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.3Hz, 1H), 5.18 (s, 1H), 4.57 (s, 2H), 4.39 (s, 1H), 3.87 (s, 3H), 2.62(s, 3H), 1.23 (s, 2H), 1.05 (s, 2H). 398 95% 6-37

Me ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 9.63 (s, 1H), 8.92 (s, 1H),8.51 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.52 (d, J = 8.3Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.43 (m, 3H), 3.94 (s, 3H), 3.43 (s,482 95% 2H), 2.80 (d, J = 24.7 Hz, 6H), 2.62 (s, 3H), 1.23 (s, 2H), 1.07(s, 2H). 6-38

Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.90 (s, 1H), 7.93 (d, J =9.2 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J = 8.0Hz, 1H), 6.13 (s, 2H), 4.38 (m, 1H), 2.62 (s, 3H), 1.23 (m, 2H), 1.05(m, 2H). 382 98% 6-39

Me ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 10.11 (s, 1H), 8.91 (s, 1H),7.97 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 1.6 Hz,1H), 6.45-6.21 (s, 2H), 4.41-4.30 (m, 1H), 2.74-2.56 (s, 3H), 1.33-1.17(d, J = 6.6 Hz, 2H), 1.12-0.96 (t, J = 3.1 Hz, 2H). 410 98% 6-40

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.53 (s, 1H), 8.90 (s, 1H),8.16 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 1.7 Hz, 1H), 7.02(d, J = 1.7 Hz, 1H), 6.21 (s, 2H), 4.48-4.16 (m, 1H), 2.64 (s, 3H),1.35- 1.21 (d, J = 6.8 Hz, 2H), 1.12-1.01 (m, 2H). 425 98% 6-41

Me ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 8.90 (s, 1H), 7.96 (d, J =8.8 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.4 (d, J = 1.6 Hz, 1H), 6.36 (s,2H), 4.52-4.26 (m, 1H), 2.63 (s, 3H), 1.35-1.15 (d, J = 6.6 Hz, 2H),1.10-0.99 (m, 2H). 407 98% 6-42

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.89 (s, 1H), 794 (d, J = 8.7Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 6.95 (d, J = 1.5 Hz, 1H), 6.22 (s,2H), 4.57- 4.46 (s, 1H), 4.42-4.30 (m, 1H), 2.63 (s, 3H), 1.33- 1.15 (d,J = 6.2 Hz, 2H), 1.12-0.90 (m, 1H). 406 95% 6-43

OMe ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.80 (s, 1H), 7.90 (d, J =9.1 Hz, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 6.13 (s, 2H), 5.31 (t, J = 5.6Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.34-4.12 (mz, 1H), 3.44 (s, 3H),1.33-0.99 (m, 4H). 428 97% 6-44

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.89 (s, 1H), 7.93 (d, J =8.7 Hz, 1H), 6.97 (s, 1H), 6.93 (s, 1H), 6.73 (dd, J = 17.7, 11.3 Hz,1H), 6.20 (s, 2H), 6.00 (d, J = 17.6 Hz, 1H), 5.49 (d, J = 11.5 Hz, 1H),4.53-4.25 (m, 1H), 2.75-2.57 (s, 3H), 1.32-1.17 (d, J = 6.7 Hz, 2H),1.11-0.89 (s, 2H). 408 95% 6-45

OMe ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.80 (s, 1H), 7.90 (d, J =9.1 Hz, 1H), 7.17 (s, 1H), 7.09 (s, 1H), 6.23 (s, 2H), 4.49 (s, 1H),4.34-4.14 (m, 1H), 3.47-3.42 (s, 3H), 1.31-0.96 (m, 4H). 422 98% 6-46

OMe ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.81 (s, 1H), 7.93 (d, J =9.1 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 6.36 (s, 2H), 4.39-4.04 (m,1H), 3.46 (s, 3H), 1.26-1.06 (m, 4H) 423 98% 6-47

OMe ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.80 (s, 1H), 7.92 (d, J =9.1 Hz, 1H), 7.30 (s, 1H), 7.19 (s, 11H), 7.17 (t, J = 56 Hz, 1H), 6.27(s, 2H), 4.33-4.17 (m, 1H), 3.45 (s, 3H). 1.29-0.97 (m, 4H). 448 92%6-48

OMe ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.80 (s, 1H), 7.93 (d, J =9.1 Hz, 1H), 7.77 (s, 1H), 7.42 (t, J = 1.4 Hz, 1H), 7.28 (t, J = 1.3Hz, 1H), 7.25 (s, 1H), 6.27 (s, 2H), 4.33-4.13 (m, 1H), 3.449 (s, 3H),1.37-0.87 (m, 4H). 441 98% 6-49

OMe ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.12 (d, J = 1.2 Hz, 1H),8.81 (s, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 6.35(s, 2H), 4.33-4.17 (m, 1H), 3.46 (s, 3H), 1.32- 0.97 (m, 4H). 426 98%6-50

OMe ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.80 (s, 1H), 7.89 (d, J =9.1 Hz, 1H), 6.83-6.80 (t, J = 1.3 Hz, 1H), 6.80-6.76 (t, J = 1.2 Hz,1H), 6.11 (s, 2H), 4.34-4.12 (m, 1H), 3.86 (s, 3H), 3.31 (s, 3H),1.26-1.02 (m, 4H). 428 98% 6-51

OMe ¹H NMR (400 MHz, DMSO) δ 14.70-14.61 (s, 1H), 8.84-8.78 (s, 1H),7.96-7.88 (d, J = 9.0 Hz, 1H), 7.14 (s, 1H), 7.13 (s, 1H), 6.33-6.22 (s,2H), 4.26- 4.18 (m, 1H), 3.46 (s, 3H), 1.20-1.11 (m, 4H). 432 95% 6-52

OMe ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.80 (s, 1H), 7.92 (d, J =9.1 Hz, 1H), 7.77 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 7.25 (s, 1H),6.27 (s, 2H), 4.22 (m, 1H), 3.44 (s, 3H), 1.17 (m, 4H). 441 85% 6-53

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 8.83 (s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.42 (s, 1H), 6.36 (s, 2H), 5.10 (m, 1H), 4.18 (m, 1H), 3.47(s, 3H), 1.82-1.63 (m, 4H). 441 98% 6-54

¹H NMR (400 MHz, DMSO) δ 14.50 (s, 1H), 11.55 (s, 1H), 8.83 (s, 1H),8.16 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 6.22(s, 1H), 5.10 (m, 1H), 4.18 (m, 1H), 3.47 (s, 3H), 1.82-1.63 (m, 4H).459 95% 6-55

¹H NMR (400 MHz, DMSO) δ 14.47 (s, 1H), 8.82 (s, 1H), 8.10 (d, J = 8.7Hz, 1H), 8.00-7.87 (m, 1H), 7.66 (t, J = 9.4 Hz, 1H), 7.37 (t, J = 8.3Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 3.81 (s,3H). 440 99% 6-56

¹H NMR (400 MHz, DMSO) δ 15.44-15.10 (s, 1H), 9.12-8.99 (t, J = 1.7 Hz,1H), 8.03-7.92 (dt, J = 8.4, 1.8 Hz, 1H), 7.67-7.56 (dd, J = 8.6, 2.5Hz, 3H), 7.16-6.98 (m, 2H), 5.03-4.89 (d, J = 7.3 Hz, 1H), 4.60-4.47 (d,J = 11.4 Hz, 1H), 4.44-4.33 (d, J = 11.5 Hz, 1H), 3.86-3.75 (t, J = 1.7Hz, 3H), 1.53- 1.42 (d, J = 6.3 Hz, 3H). 352 99%

TABLE 7

Com- pound MS No. R¹⁸ = R² = NMR (MH⁺) HPLC 7-1 H Me ¹H NMR (400 MHz,DMSO) δ 14.74 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.80 344100% (s, 2H), 7.27 (s, 1H), 4.39 (s, 1H), 2.68 (s, 3H), 1.23 (s, 3H),1.03 (s, 2H). 7-2

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 9.37 (s, 2H), 8.91 (s, 1H),7.96 (d, J = 8.9 Hz, 1H), 7.87 (s, 1H), 7.51 (s, 1H), 4.43 (s, 3H), 3.00(d, J = 6.2 Hz, 2H), 2.71 (s, 3H), 1.24 (d, J = 6.4 Hz, 5H), 1.03 (s,2H). 401  95% 7-3

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 13.87 (s, 1H), 8.91 (s, 1H),7.98 (d, J = 8.1 Hz, 2H), 7.60 (s, 1H), 4.41 (s, 1H), 2.70 (s, 3H), 1.23(s, 2H), 1.06 (s, 2H). 412 100% 7-4 CH₂CN Me ¹H NMR (400 MHz, DMSO) δ14.75 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.76 383  97% (s,1H), 7.22 (s, 1H), 5.76 (s, 2H), 4.40 (m, 1H), 2.69 (s, 3H), 1.23 (m,2H), 1.04 (s, 2H). 7-5 CHO Me ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H),10.03 (s, 1H), 8.92 (s, 1H), 8.39 (s, 1H), 372  98% 8.23 (s, 1H), 7.99(d, J = 9.1 Hz, 1H), 4.42 (s, 1H), 2.71 (s, 3H), 1.24 (d, J = 6.4 Hz,2H), 1.05 (s, 2H). 7-6

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.34 (d, J = 16.3 Hz, 1H),8.90 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.78 (s, 1H), 7.42(d, J = 14.9 Hz, 1H), 4.40 (s, 1H), 2.71 (s, 3H), 1.24 (d, J = 5.8 Hz,2H), 1.04 (s, 2H). 387  96% 7-7

Me ¹H NMR (400 MHz, DMSO) δ 13.57-13.17 (m, 1H), 11.49 (s, 1H), 9.30 (s,1H), 8.77 (s, 1H), 8.09 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.83 (s, 1H),4.33 (s, 1H), 2.66 (s, 3H), 1.22 (d, J = 7.5 Hz, 2H), 0.97 (s, 2H). 403100% 7-8 CONH₂ Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.91 (s, 1H),8.12 (s, 1H), 7.98 (m, 2H), 387 100% 7.89 (s, 1H), 7.57 (s, 1H), 4.41(s, 1H), 2.71 (s, 3H), 1.25 (d, J = 5.7 Hz, 2H), 1.03 (s, 2H). 7-9 CO₂HMe ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 13.34 (s, 1H), 8.91 (s, 1H),8.12 (s, 1H), 388 100% 7.96 (d, J = 8.7 Hz, 1H), 7.86 (s, 1H), 4.40 (s,1H), 2.69 (s, 3H), 1.24 (d, J = 6.2 Hz, 2H), 1.05 (s, 2H). 7-10

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 12.49 (s, 1H), 8.87 (s, 1H).7.96 (d, J = 11.9 Hz, 2H), 7.81 (d, J = 15.8 Hz, 1H), 7.69 (s, 1H), 6.30(d, J = 15.7 Hz, 1H), 4.40 (s, 1H), 2.71 (s, 3H), 1.24 (d, J = 6.4 Hz,2H), 1.04 (s, 2H). 414  95% 7-11

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.92 (s, 1H), 8.13 (s, 1H),8.00 (d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 4.42 (s, 1H), 2.74 (s, 3H), 1.24(s, 2H), 1.06 (s, 2H). 412 100% 7-12

Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 11.75 (s, 1H), 8.90 (s, 1H),7.97 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H),7.00 (s, 2H), 4.41 (s, 1H), 4.17 (d, J = 6.9 Hz, 2H), 2.75 (s, 3H), 1.99(s, 2H), 1.23 (s, 3H), 1.04 (s, 2H), 0.85 (s, 2H). 481 100% 7-13

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.91 (s, 1H), 8.49 (s, 1H),7.97 (d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 7.64 (s, 2H), 4.41 (s, 1H), 2.73(s, 3H), 1.25 (d, J = 6.5 Hz, 2H), 1.05 (s, 2H). 411  95% 7-14

Me ¹H NMR (400 MHz, DMSO) δ 14.90-14.46 (m, 1H), 8.93 (s, 1H), 8.05 (s,1H), 8.02 (d, J = 8.4 Hz, 2H), 7.63 (s, 2H), 7.28 (s, 2H), 4.44 (s, 1H),2.78 (s, 3H), 1.27 (d, J = 6.4 Hz, 2H), 1.07 (s, 2H). 460 100% 7-15

Me ¹H NMR (400 MHz, DMSO) δ 6.92 (s, 1H), 8.07 (d, J = 6.7 Hz, 2H), 7.99(d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.54 (s, 3H), 4.42 (s,1H), 2.76 (s, 3H), 1.25 (d, J = 6.0 Hz, 3H), 1.07 (m, 2H). 487  95% 7-16

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (b, 1H), 13.75 (s, 1H), 8.90 (s, 1H),7.96 (d, J = 8.9 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 4.47-4.32 (m, 1H),2.73 (s, 3H), 2.41 (s, 3H), 1.25 (t, J = 6.3 Hz, 2H), 1.07 (s, 2H). 425 98% 7-17 CN OMe ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 8.80 (s, 1H),8.42 (s, 1H), 7.28 (s, 1H), 385  98% 7.96 (d, J = 9.2 Hz, 1H), 4.47-4.32(m, 1H), 3.47 (s, 3H), 1.23-1.15 (m, 4H). 7-18

OMe ¹H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.72 (s, 2H), 7.58 (s, 1H),7.43 (d, J = 9.7 Hz, 1H), 4.13 (m, 1H), 3.27 (s, 3H), 2.20 (s, 3H),1.05-0.81 (m, 4H). 441  98% 7-19

Cl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.86(s, 1H), 7.67 (s, 1H), 4.13 (m, 1H), 2.40 (s, 3H), 1.24-1.12 (m, 4H).445  85%

TABLE 8-1

Compound MS No. R¹⁹ = R² = (MH⁺) 8-1 H Me 352.36 8-2 3-NH2 Me 337.34 8-34-F Me 355.33 8-4 4-CO2H Me 381.35 8-5 2-NH2 Me 352.36 8-6 3-Me Me351.37 8-7 4-Me Me 351.37 8-8 2,3-Dimethyl Me 365.4  8-9 2-Cl Me 371.798-10 4-Cl Me 371.79 8-11 3-CO2H Me 381.35 8-12 3-CF3 Me 405.34 8-133,4-Dichloro Me 406.23 8-14 3-F Me 355.33 8-15 4-tBu Me 393.45 8-164-MeO Cyclopropyl 393.41 8-17 4-Ph Me 413.44 8-18 4-NO2 Me 382.34 8-193,4-Dichloro MeO 404.24 8-20 4-MeO Me 365.38 8-21 3,4-Dimethyl Me 365.4 8-22 4-CF3 Me 405.34 8-24 3-CONH2 Me 380.37 8-25 4-NH2 Me 352.36 8-264-OH Me 353.34 8-27 4-OMe F 353.34 8-28 4-OMe NO2 398.34 8-29 4-OMe Cl387.79 8-30 4-OMe NH2 368.36 8-31 4-OMe Br 432.24 8-32 4-OMe H 353.348-33 4-OMe CN 378.35 8-34 4-OMe CH2F 385.36 8-35 4-OMe MeO 383.37 8-364-OMe CH2Br 446.27 8-37 4-OMe CH2OH 383.37 8-38 4-OMe CHF2 403.35 8-394-Amino-3-hydroxy Me 368.36 8-40 4-OMe CHO 381.35 8-41 4-OMe C≡CH 377.378-42 4-OMe Et 381.4  8-43 4-OMe CH═CH2 379.38 8-44 3,4-Diamino Me 367.378-45 4-Amino-3-nitro Me 397.36 8-46 4-Methylamino-3-nitro Me 411.38 8-473-Dimethylamino Me 380.41 8-48 2,4-Dinitro-3- Me 470.41 dimethylamino8-49 4-Nitro-3-dimethylamino Me 425.41 8-50 2-Nitro-3-dimethylamino Me425.41 8-51 4-Dimethylamino-3-nitro Me 425.41 8-52 4-Ethylamino-3-nitroMe 425.41 8-53 4-Dimethylamino Me 380.41 8-54 3-Formyl-4-nitro Me 410.358-55 4-Amino-3-nitro Me 413.36 8-56 3-Fluoro-4-nitro Me 400.33

TABLE 8-2

Compound MS No. R³ = R² = (MH⁺) 8-57

Me 451.45 8-58

Me 465.47 8-59

Me 480.49 8-60

Me 495.48 8-61

Me 508.54 8-62

Me 452.44 8-63

Me 456.46 8-64

Me 467.45 8-65

Me 411.38 8-66

Me 415.35 8-67

Me 425.41 8-68

Me 429.37 8-69

Me 426.35 8-70

Me 454.45 8-71

Me 449.39 8-72

Me 454.45 8-73

Me 463.42 8-74

Me 447.46 8-75

Me 406.45 8-76

Me 421.46 8-77

Me 418.42

TABLE 9

Compound MS No. R³ = R² = (MH⁺) 9-1

Me 407.19 9-2

Me 404.39 9-3

Me 394.35 9-4

Me 397.4  9-5

Me 392.38 9-6

Me 326.32 9-7

Me 326.32 9-8

Me 394.4  9-9

Me 380.41 9-10

Me 395.43 9-11

Me 355.36 9-12

Me 393.37 9-13

Me 327.31 9-14

Me 406.2  9-15

Me 409.43 9-16

Me 372.3  9-17

Me 328.34 9-18

Me 397.44 9-19

Me 354.33 9-20

Me 354.33 9-21

Me 422.33 9-22

Me 342.36 9-24

Me 411.47

Experimental Example 1 In Vitro Antibacterial Activity

All compounds were dissolved in dimethyl sulfoxide (DMSO, Merck,purity >99.9%) to achieve final 1 mg/ml desired concentrations.

MICs (minimum inhibitory concentrations) were determined by the brothmicrodilution technique with 96-well microdilution plates. Theantimicrobials were tested using the following MIC ranges: 0.008 to 8μg/ml. The plates were filled with 100 μl of reinforced clostridialmedium (Oxoid; Unipath Ltd., Basingstoke, United Kingdom) per wellcontaining the final antibiotic concentrations. The plates were thawedand preincubated for 3 hours in an anaerobic chamber (Thermal, USA)containing an atmosphere of 80% N₂, 15% CO₂, and 5% H₂. The bacterialinocula were prepared by suspending growth from 48 hours cultures inreinforced clostridial medium. The final inoculum was approximately1.0×10⁵⁻⁶ CFU/well. The plates were incubated for 48 hours at 37° C. inthe anaerobic chamber. The MIC was defined as the lowest antibioticconcentration that inhibited visible growth. Ciprofloxacin, vancomycinand metronidazole were used as a positive control. The results are shownin Table 10.

TABLE 10 MIC of example compounds against C. difficile (μg/mL) Com-pound C. difficile C. difficile C. difficile C. difficile No. ATCC43255ATCC7000057 ATCC70092 IQCC23903 2-18  0.016-0.063 0.016-0.063≲0.008-0.063   0.032-0.063 2-46  0.032-0.125 0.032-0.25  0.063-0.250.125-0.25 5-14 0.125-0.25 0.125-0.5  0.125-0.25 0.125-0.5  2-490.063-0.25 0.063-0.25  0.063-0.5  0.063-0.25 3-11 ≲0.008-0.032 0.016-0.032 ≲0.008-0.032  ≲0.008-0.063  2-31 ≲0.008-0.032  0.016-0.032 0.016-0.032  0.016-0.063 1-2   0.032-0.125 0.032-0.125  0.032-0.1250.063-0.25 3-21  0.016-0.032 0.016-0.063  0.016-0.063  0.032-0.063 2-38 0.016-0.032 0.016-0.032  0.032-0.063  0.016-0.032 3-30  0.032-0.0630.063-0.125  0.063-0.125 0.063-0.25

Experimental Example 2 In Vivo Antibacterial Efficacy

In vivo efficacy was evaluated in a hamster intestinal infectiontreatment model. Male Golden Syrian hamsters were purchased from CharlesRiver Laboratories (Kingston, N.Y., USA) and were about 6 weeks of age,with weights ranging from 80 to 100 g at the start of the study. Theanimals were housed individually in filtered polycarbonate shoe-boxstyle cages equipped with water bottles, and Harlan Toklab Global Diet2016 was available ad libitrum via food hoppers. The hamsters werepre-treated with clindamycin (1 mg/kg, p.o.) and vancomycin (50 mg/kg,p.o.), formulated in arabic gum, at Day 0. At Day 7, each hamster wasinoculated via oral gavage with 0.5 mL of a suspension of C. difficileATCC 43255 (10⁵ CFU/body, p.o.). To prepare this inoculum, C. difficilewas grown in GAM agar (Japan) for 5 days at 37° C., and the bacteriawere harvested by centrifugation, rinsed twice with arabic gum,resuspended in arabic gum and the exact bacteria density was determinedusing the dilution plate count method. Oral dosing of compounds,pulverized and formulated in arabic gum was commenced the following day(Day 8). Treatments were administered once a day for 5 consecutive daysat specified doses (10, 2, and 0.4 mg/kg), with five hamsters per group.Controls were included an uninfected group and an infected but untreatedgroup, and vancomycin was used as positive control. The hamsters wereobserved daily to record clinical signs (duration, time of onset, timeof recovery or death), and animals in a lethargic, clearly moribundstate were euthanized. A necropsy was performed on animals that wereeither found dead or were euthanized at the end of the study (37 days).The results are shown in FIG. 1 and FIG. 2.

Preparation Example 1

An injection preparation is prepared from the following components.

Components Amount Compound 1-2 200 mg Glucose 250 mg Distilled water forinjection g.s. Total 5 ml

Compound I-2 and glucose are dissolved in distilled water for injection,and the solution is added to a 5 ml ampoule, which is purged withnitrogen gas and then subjected to sterilization at 121° C. for 15minutes to give an injection preparation.

Preparation Example 2

Film coated tablets are prepared from the following components.

Components Amount Compound 2-18 100 g Avicel (registered trademark) 40 gCorn starch 30 g Magnesium stearate 2 g TC-5 (registered trademark) 10 gPolyethylene glycol 6000 3 g Castor oil 40 g Ethanol 40 g

Compound 2-18, Avicel (registered trademark of microcrystallinecellulose, manufactured by Asahi Kasei Corporation, Japan), corn starchand magnesium stearate are mixed and kneaded, and the mixture istabletted using a conventional pounder (R 10 mm) for sugar coating(manufactured by Kikusui Seisakusho Ltd., Japan). The tablets thusobtained are coated with a film coating agent consisting of TC-5(registered trademark of hydroxypropyl methylcellulose, manufactured byShin-Etsu Chemical Co., Ltd., Japan), polyethylene glycol 6000, castoroil and ethanol to give film coated tablets.

Preparation Example 3

An ointment is prepared from the following components.

Components Amount Compound 3-11 2 g Purified lanolin 5 g Bleachedbeeswax 5 g White petrolatum 88 g Total 100 g

Bleached beeswax is made liquid by heating, and thereto are addedcompound 3-11, purified lanolin and white petrolatum, and the mixture isheated until it becomes liquid. The mixture is stirred until it issolidified to give an ointment.

1-27. (canceled)
 28. A compound selected from the group consisting ofcompounds represented by the following formulae

or a salt thereof.
 29. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 30. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 31. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 32. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 33. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 34. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 35. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 36. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 37. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 38. The compound of claim 28, which is a compoundrepresented by the formula

or a salt thereof.
 39. A pharmaceutical composition comprising acompound of claim 28 or a salt thereof and a pharmaceutically acceptablecarrier.
 40. An antimicrobial agent comprising a compound of claim 28 ora salt thereof.
 41. A method for treating a bacterial infection whichcomprises administering an effective amount of a compound of claim 28 ora salt thereof to a human or an animal.